# Presentation: 417075

## CDRH Panel Meeting June 22, 2005

**Ileana L. Pi****ña, M.D.**
- Professor of Medicine
- Case Western Reserve University
- Director Heart Failure/Transplantation
**Julie Swain, M.D**.
- Cardiovascular Surgeon
- Consultants
- Clinical Reviewers for PMA P040049

- FDA Clinical Review

- Panel Presenation

## Intended Use of the CorCap

- “...provides beneficial changes in cardiac structure associated with a reverse remodeling effect as defined by a reduction in LV size, an increase in EF and a change to a more elliptical shape.  ...provides a decrease in the need for additional major cardiac procedures associated with the progression of HF and an overall improvement in QOL.”

- FDA Clinical Review

- Panel Presenation

## CorCap Clinical Trial

- Prospective
- Randomized
- Controlled
- 2-arm trial (heart failure patients either with mitral insufficiency requiring MVR or without mitral insufficiency) stratified by MVR

- FDA Clinical Review

- Panel Presenation

## CorCap Clinical Trial

- Hypothesis:
- 	The CorCap would improve patient functional status as measured by a clinical composite consisting of
***mortality**** *
***major cardiac procedure for worsening heart failure (MCP)**** *
***change in NYHA Class***

- FDA Clinical Review

- Panel Presenation

## CorCap Clinical Trial

***Primary Objective:***
**	****To compare the functional status after a minimum of 12 months of follow-up for patients randomly assigned to Treatment (CorCap) or Control (no CorCap).**
***Secondary Objective*****:  ****To determine the rate of death and other SAE’s experienced by  patients randomized to CorCap implant and to compare this rate with that for patients assigned to the control group.  ****To compare patient functional status and structural changes in the heart for the Treatment and the Control groups.**

- FDA Clinical Review

- Panel Presenation

## CorCap Clinical Trial

**Primary Composite Efficacy Endpoint:  **
-         C**omposite endpoint of :**
***all-cause mortality***
***NYHA class as per core lab ***
***Major Cardiac Procedures (MCP) indicative of progression of HF. ***

- FDA Clinical Review

- Panel Presenation

## CorCap Clinical Trial

**Secondary Efficacy Endpoints: **
**Reduction in LV size, LV function and re-shape of the LV**
**Functional status:  Improvement in QOL at 6 and 12 months (MLWHF, SF36), exercise status 6 and 12 months (6 min walk, CPX testing ) and site-determined NYHA**
**Changes in CPX , Peak VO2, VT, and exercise time at 6 and 12 mo**
**Changes in BNP**
**All cause mortality and hospitalizations**
**Incidence of  Major Cardiac Procedures**
**Safety:  hospitalization, adverse events, major cardiac**** ****procedures and mortality**
**# of hospitalizations, hospital days and ICU days**

- FDA Clinical Review

- Panel Presenation

## Baseline Characteristics

| Parameter | Value |
| --- | --- |
| Age | 52.5 years |
| Men | 55.3% |
| Caucasian | 65% |
| Etiology :  Ischemic | 10% |
| Non-ischemic (dilated) | 81.6% |
| Valvular | 11.3% |
| EF | 27.4% |
| LVEDD | 7.2 cm |
| Peak VO2 | 15.0 ml/min/kg |
| 6 min walk | 340.9 m |
| MLWHF | 59.3 |

- FDA Clinical Review

- Panel Presenation

## Missing Data

- Missing tests occurred in 47% of patients.
- In the **Treatment arm**, 59% of patients did not have a baseline CoreLab NYHA assessment.
- In the **Control arm**, 57% of the patients did not have a baseline CoreLab NYHA assessment.

- FDA Clinical Review

- Panel Presenation

## Results: Primary Composite Endpoint

|  | Treatment
(Average %) | Control
(Average %) | Odds Ratio
T/C
(95% CI) | P-value |
| --- | --- | --- | --- | --- |
| Improved | 37.7 | 27.3 | 1.73 (1.07-2.79) | 0.024 |
| Same | 25.1 | 27.7 |  |  |
| Worsened | 37.2 | 45.1 |  |  |

- FDA Clinical Review

- Panel Presenation

## Mortality (as of April 15, 2005)

**% of patients**

- FDA Clinical Review

- Panel Presenation

**Notes:**
There were 7 patients who died within the first 30 days of surgery in the Treatment group and 1 in the Control group,.  One patient of the 7 in the Treatment group died prior to surgery on the evening of randomization.  Therefore, the true perioperative mortality is 4.3% in the Treatment arm. 

## 30 Day Operative Mortality by YearNoMVR Stratum

- FDA Clinical Review

- Panel Presenation

**Notes:**
Possible causes of decrease:  learning curve vs patient selection bias
Ileana 

## Hospitalized Patients for HF

**	****	****	****	****	**** ****REMATCH**
**           ****	**** ****	**** ****VMAC ****	****OPT****	**** FIRST ****	**** OMM ****	****   ****ESCAPE****       ****CorCap**
**	****	****	****	****	****	****	****    ****Control**
**	**
**SBP ****	****	****121 ****	****120 ****	**** 107 ****	**** 103 ****	****    106****	****    ****111**
**	**
**LVEF ****	****	****26% ****	****24% ****	****19% ****	**** 17%           <30%****	****    ****27.3**
**	**
**Na ****	****	****	****138 ****	****138 ****	**** 135 ****	****    136.7****	**
**	**
**6 mo ****	****	****23% ****	****10% ****	****37% ****	**** 48% ****	****     19%****	****    ****7.7%**
**Mortality ****	****	****	**** ****	****	****	****	**

***Adapted from LW Stevenson, presentation for REMATCH***

- FDA Clinical Review

- Panel Presenation

##                              1 year Mortality   Study                     Control   vs    Tx 	

**	**
**	****  **
**	****SOLVD ****	****	****	****14 ****	****vs ****	****11 ****	****	****	**
**	****(ACE Inhibitor) ****	****	****	****	****	****	**
**	****CONSENSUS ****	****	****62 ****	****vs ****	****45 ****	****	****	**
**	****(ACE Inhibitor) ****	****	****	****	****	****	**
**	****COPERNICUS ****	****	****18.5 ****	****vs ****	****11 ****	****	****	**
**	****(Beta Blocker) ****	****	****	****	****	****	**
**	****RALES ****	****	****	****25 ****	****vs ****	****17 ****	****	****	**
**	****(Spironolactone) ****	****	****	****	****	****	**
**	****REMATCH ****	****	****76 ****	****vs ****	****49 ****	****	****	**
**	****(LVAD) **
**	****ESCAPE****	****	****	****17.4****	****vs.****	****20.9****	****	****	****	****	****         ****	****(6 mos)**
**	****CorCap****	****	****	****14****	****vs.****	****13****	**
**	**

***Adapted from LW Stevenson, presentation for REMATCH***

**                             ****1 year Mortality ****  ****Study****                    **** Control   vs    Tx ****	**

- FDA Clinical Review

- Panel Presenation

## Concerns

**There are remaining concerns regarding:**
**Disagreement with CERC Adjudication of several MCP’s**
**Bias against re-op of pts with CorCap**
**NYHA Class for Status II Transplant patients**
**Reverse remodeling**
**Significance of BNP**
**Clinical relevance of MLWHF differences**

- FDA Clinical Review

- Panel Presenation

## Major Cardiac Procedures

**Major Cardiac Procedures (MCP) were defined as surgical interventions for worsening heart failure including CABG, MVR, TVR and BiV pacing.**
**Progression of heart failure**
**Hx and P.E.**
**Decreased exercise tolerance, JVD, rales**
**CXR**
**Laboratory Studies**
**Right Heart Cath**
**Lack of Clinical Response to Conservative Rx **

- FDA Clinical Review

- Panel Presenation

**Notes:**
A CERC adjudicated all MCP’s in this trial.  The Committee determined that of 41 MCP’s reviewed, 9 were not associated with “worsening HF” and therefore are not counted as qualifying for “worsening” in the endpoint.  Of the 9 MCP’s 8 were in the Control Group and 1 in the Treatment Group.  Of the 9 MCP’s, 7 were BiV pacing implantation, 1 was mitral valve surgery and 1 was tricuspid valve surgery.

## Major Cardiac Procedures: MVR Stratum

|  | Treatment
(n=91) |  |  | Control
(n=102) |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | # Pts | # Events | Rate | # Pts | # Events | Rate | HR (T/C)
(95% CI) | p-value
 |
| Cardiac Transplant | 6 | 6 | 3.8 | 10 | 12 | 6.2 | 0.63
(0.23, 1.74) | 0.37 |
| LVAD | 3 | 3 | 1.9 | 6 | 7 | 3.6 | 0.57
(0.14, 2.28) | 0.43 |
| MVR  | 1 | 1 | 0.6 | 3 | 3 | 1.8 | NA
  | NA |
| Bi-Ventricular Pacing  | 6 | 6 | 3.8 | 7 | 8 | 4.3 | 0.75
(0.24, 2.36) | 0.62 |
| TVR    | 0 | 0 | 0.0 | 2 | 2 | 1.2 | NA
  | NA |
| Any of above procedures | 14 | 16 | 9.3 | 21 | 32 | 14.2 | 0.57
(0.28, 1.16) | 0.12 |

- FDA Clinical Review

- Panel Presenation

**Notes:**
The Agency has also reviewed the operative reports (by surgeons)  of patients with MCP’s and disagrees with the CERC in the classification of worsening HF in several patients. 

This reviewer has carefully read both summaries and continues to disagree with the assement of “worsening HF” which implies worsening LV function.  Both patients had mitral stenosis with significant valve gradients.  One patient needed to return to the OR months later for fungal endocarditis of the tricuspid valve.
The Sponsor has also provided clinical summary data on an additional 2 patients who received cardiac transplants and a brief note on another patient who expired prior to end of study..
  Although the clinical summary on one patient (MVR Control group) describes that “it seems unlikely that the transplant was due to a problem with the initial mitral valve procedure”, the surgical report states that the “patient redeveloped severe MR from a ____tethering of the posterior leaflet.  Therefore, in the opinion of the surgeon, the worsening HF was due to worsening MR from tethering of the posterior leaflet. 
The clinical summary provided states that post op the patient (MVR Control) suffered a pulmonary embolism followed by cardiogenic shock.  The surgical report confirms this as well.  Although the patient had “cardiogenic shock”, this clinical presentation requiring another procedure (transplant)  is not due to progressive HF as is the intent of the CorCap study to prevent.
The third patient had mitral valve and tricuspid valve repair.  2 months later, developed severe TR and was returned to the OR for tricuspid valve surgery.

## Major Cardiac Procedures: NoMVR Stratum

|   | Treatment |  |  | Control |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  | # patients | # events | Rate | # patients | # events | Rate | p value |
| Cardiac
Transplant | 1 | 1 | 1.1 | 6 | 6 | 7.5 | 0.06 |
| LVAD | 0 | 0 | 0 | 2 | 2 | 2.4 | NA |
| MVR  | 0 | 0 | 0 | 0 | 0 | 0 | NA |
| Bi-Ventricular
Pacing  | 4 | 4 | 4.0 | 7 | 8 | 9.2 | 0.24 |
| TVR    | 0 | 0 | 0 | 0 | 0 | 0 | NA |
| Any of above
procedures | 5 | 5 | 5.8 | 12 | 10 | 16.8 | 0.03 |

- FDA Clinical Review

- Panel Presenation

## CRT (BiV Pacing) and Open Procedures by Group

**% of patients**

- FDA Clinical Review

- Panel Presenation

**Notes:**
CRT became available during this study.  CRT insertion is presumably prompted by worsening heart failure, a QRS >120 msec, and appropriate maximized medical therapy.  More patients received CRT in the control group (14 patients) than in the treatment group (10 patients).  CRT could have been offered as concomitant therapy to patients who could not crossover to the treatment arm. 
Note that the proportionally the NoMVR treatment group had more CRT than open proceudres perhaps reflecting selection bias. 

## Cardiac Transplant Status

| Group | NoMVR 
Control |  | MVR
Control | MVR
Treatment |
| --- | --- | --- | --- | --- |
| UNOS Status | Ib  | II | II | Ib |
| Months  enrollment to transplant  | 8 | 13 | 6 | 9 |

- FDA Clinical Review

- Panel Presenation

**Notes:**
Twenty three patients received a heart transplant: 6 patients in the MVR + CorCap group, 1 in the NoMVR CorCap Group, 10 in the MVR Control group and 6 in the NoMVR Control group.  Of 6 LVAD’s in the MVR-Control group, 4 were followed by a transplant during the follow-up period.  One patient in the Treatment group had a subsequent transplant during the follow-up period.  
In 19 of the 23 patients, the date of listing is after the date of randomization.  Four patients were listed for transplant prior to randomization.  Three of these patients, (all as Status II), were enrolled under the Revision 3 protocol which did not exclude patients on the transplant list.  The fourth patient  was considered UNOS Status 7 (inactive) at the time of enrollment.

As per Sponsor, there were three patients (all MVR control) who were listed within 30 days of their initial surgery.  One of those 3 patients was classified as worsening HF and adjudicated as such.  This was likely due to complications that occurred with the initial surgery. Excluding those 3 patients, the average time to transplant was 12.11 months.  

UNOS Status Ia is in hospital on inotropes, Ib on inotropes no hemodynamic monitoring (could be at home) Status II at home with no constant inotropes or hemodynamic monitoring.
Three patients (two Treatment and one Control) were made Status 7 because of improvements in functional capacity.  Both Treatment patients were subsequently transplanted.

## LVAD as MCP

- None of the 11 patients who received an LVAD were listed for transplantation prior to enrollment
- 6  were listed prior to LVAD insertion as a bridge to transplant
- 3 patients were not on the transplant list
- 2 were listed after the LVAD was placed
- 3 patients who received LVAD’s were never listed for transplant

- FDA Clinical Review

- Panel Presenation

## Functional Measures

- Placebo effect possible in less objective measures
- QOL
- NYHA, site assessed
- Placebo effect less likely in objective measures of function
- VO2
- 6 min walk

- FDA Clinical Review

- Panel Presenation

## NYHA by Core Lab

- FDA Clinical Review

- Panel Presenation

**Notes:**
No MVR Treatment (n=26, 46%)No MVR Control (n=19, 38%)MVR Treatment (n=35, 38%)MVR Control (n=41, 40%)Improved1141714Same810912Worsened75915

## NYHA-Site Assessed

- FDA Clinical Review

- Panel Presenation

**Notes:**
A greater number of patients improved in the no MVR treatment group than in the NoMVR control.  A greater number of patients improved in the MVR Control vs. MVR Treatment and more patients were unchanged in the MVR treatment group vs. control. 

## QOL by MLWHF

| NoMVR
Stratum | Treatment
(n=57) |  | Control
(n=50) |  |
| --- | --- | --- | --- | --- |
|  | # Patients | Mean Change
(95% CI) | # Patients | Mean Change
(95% CI) |
| 12 Months | 45 | -11.3
(-17.1, -5.5) | 42 | -6.4
(-12.4, -0.3) |

| MVR Stratum | Treatment
(n=91) |  | Control
(n=102) |  |
| --- | --- | --- | --- | --- |
|  | # Patients | Mean Change
(95% CI) | # Patients | Mean Change
(95% CI) |
| 12 Months | 80 | -21.9
(-26.9, -16.9) | 77 | -18.3
(-23.3, -13.3) |

- FDA Clinical Review

- Panel Presenation

**Notes:**
Quality of Life was assessed by the Minnesota Living with Heart Failure Instrument (MLWHF).  Lower scores are interpreted as a better QOL.  At 12 months there were 125 (84%) QOL assessments in the Treatment group and 119 (78%) in the Control group.  Both groups improved their QOL scores.  The Treatment group had a reduction at 12 months of 16.4 units vs 12.6 units in the Control group.  Both groups, therefore, improved QOL. The difference between the 2 groups of 3.8 units is not clinically meaningful.  
Note the difference between the groups is not clinically meaninful.  As in AHeft

## 6 minute walk

- FDA Clinical Review

- Panel Presenation

**Notes:**
77 patients had no 6 min walk data 
In the MVR stratum group, 75/91 patients (82%) had data at baseline and 12 months in the treatment arm and 54/100 (54%) had data at baseline and 12 months in the control arm
In the NoMVR stratum, 40/57 (70%) patients had data at baseline and 12 months in the treatment arm and 30/50 (60%) had data at baseline and 12 months in the control arm.
The graph below divides the patients according to stratum and by changes in distance >65 m or 0-65 m or decrease. The patients who died and those who had an MCP within 12 months are included in the decreased group.

## CPX data, peak VO2

- FDA Clinical Review

- Panel Presenation

**Notes:**
.  75/152 (49%) control patients had VO2 data at baseline and 12 months follow-up and 90/148 (61%) treatment arm patients had baseline VO2 and followup data.

Therefore, the results of functional testing are inconsistent with a marked clinical improvement with the CorCap.

Control group started at a lower VO2.

## Functional Summary

**Placebo effects are most likely in subjective testing, such as QOL and NYHA Class.  **
**Neither 6 min walk nor CPX testing showed clinically significant improvements in the CorCap group.**

- FDA Clinical Review

- Panel Presenation

## Structural Endpoints (at 12 mos)

|  | Treatment 
(n=132) | Control 
(n=134) |
| --- | --- | --- |
| LVEDV(ml) | -32.7(n=97) | -17.2 (n=88) |
| LVESV(ml) | -25.9(n=97)  | -8.2 (n=88) |
| LV EF(%) | 3.7 | 0.2 |
| Sphericity | 0.10 | 0.03 |
| LV mass gm/m2 | -14.9 (n=50) | -13.6 (n=53) |
| LVEDD(mm) | -5.8 (n=114) | -3.6 (n=107) |
| LVESD(mm) | -4.8 (n=114) | -2.5 (n=105) |

- FDA Clinical Review

- Panel Presenation

## Structural Endpoints (at 12 mos)

**(n=64/91)       (n=60/102)****	****   (n=33/57)        (n=28/50)**

- FDA Clinical Review

- Panel Presenation

## Reverse Remodeling?

**Treatment**
**At  6 mos, 30% pts with no data**
**At 12 mos, 34% pts with no data**

**Control**
**At 6 mos,  37%  pts with no data**
**At 12 mos, 42%  pts with no data**

- FDA Clinical Review

- Panel Presenation

## Reverse Remodeling?

**Data are missing—not at random with more data missing in the Control group**
**Remodeling is a time related process**
**Should be linked to favorable outcome**
**No difference in mortality**
**Most changes occur early post CorCap application**
**Less likely to be true reverse remodeling**
**Most of the LV mass decrease is accounted for by the MVR procedure**

- FDA Clinical Review

- Panel Presenation

## Previous Clinical Experience (not published) (Charité)

- Single center, non randomized
- 29 patients
- 17 with other valve surgery
- 12 with CorCap only
- Baseline imbalances in sickness severity (duration of HF, beta blocker, #hospitalizations)
- 4 in-hospital deaths

- FDA Clinical Review

- Panel Presenation

## Clinical Experience (Charité)

**10**

**10**

**8**

**10**

**9**

**10**

**11**

**11**

**8**

**10**

**10**

**10**

**Values are averages**

- FDA Clinical Review

- Panel Presenation

## Clinical Experience (Charité)

- FDA Clinical Review

- Panel Presenation

## Brain Natriuretic Peptide (BNP)

- FDA Clinical Review

- Panel Presenation

## Structural Summary

**Structural Changes support most of the benefit in LV mass reduction due to MVR and not to the CorCap + MVR.**
**Structural changes occur by 3 mos suggestive of an early effect and not reverse remodeling which should occur and improve with time (beyond 3 months).**
**The BNP measures do not support an improvement in filling pressures in the T arm.**
**Correlations between structural and functional changes are difficult to interpret due to large amounts of missing data particularly in CPX testing and 6’ walk.  Missing data may not be at random.**

- FDA Clinical Review

- Panel Presenation

## Adverse Events Related to Hemodynamic Compromise

**p =0.053     p =0.14**

- Treatment group n=148
- Control group n=152

- FDA Clinical Review

- Panel Presenation

## <30 days SAE’s

|  | NoMVR |  |  | MVR |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | Control | Treat | p | Control | Treat | p |
| Hemodynamic compromise | 5 | 18 | 0.007 | 24 | 21 | 0.95 |
| Infection | 0 | 6 | 0.03 | 13 | 18 | 0.23 |
| Neurologic
deficit | 0 | 1 | 1.0 | 2 | 5 | 0.23 |
| Pulmonary
Compromise | 0 | 7 | 0.01 | 12 | 17 | 0.19 |
| Any SAE/Death | 7 | 31 | 0.0001 | 54 | 51 | 0.74 |

- FDA Clinical Review

- Panel Presenation

## Constrictive Physiology

- 252 patients had echo data
- 18 patients in the Treatment arm and 30 in the Control arm without follow-up echo.
- 43 patients (33%) in the Treatment group and 16 patients (13%) in the Control group with at least 1 echo with possible or suggestion of constriction (p=0.0002).
- No patient had any action taken nor are there any AE’s related to constriction.
- There is more early hemodynamic compromise in the Treatment group when compared to Control, but no evidence of constriction at 18 months

- FDA Clinical Review

- Panel Presenation

## Clinical Summary

**The Sponsor has met the primary endpoint.**
**The only component contribution of the primary endpoint that is significant is the MCP. **
**There are no differences in mortality or rehospitalizations.**
**There are large amounts of missing data which may not be at random, including baseline core lab NYHA Class.**

- FDA Clinical Review

- Panel Presenation

**Notes:**
At least 3 MCP’s may have arisen from other than progressive worsening HF.

## Clinical Summary (cont)

**Unblinded trial with potential problems of known and unknown treatment and assessment bias.**
**Upfront mortality cost to the device, with modest long term benefit.**
**Only 10% of the patients tested had an ischemic etiology for HF. **

- FDA Clinical Review

- Panel Presenation

- FDA Clinical Review

- Panel Presenation

## Structural Endpoints (at 12 mos)

|  | MVR
Treatment           Control
(n=91)                      (n=102) |  | noMVR
Treatment                  Control
(n=57)                           (n=50) |  |
| --- | --- | --- | --- | --- |
| LVEDV | -39.9(n=64) | -25 (n=60) | -25.9 (n=33) | -12.4 (n=28) |
| LVESV | 0.1(n=64) | 0 (n=60) | -23.6 (n=33) | -6.0 (n=28) |
| LV EF | 2.9 (n=64) | -1.2 (n=60) | 4.4 (n=33) | 1.5 (n=28) |
| Sphericity | 0.12 (n=63) | 0.03 (n=58) | 0.08 (n=34) | 0.04 (n=29) |
| LV mass | -20.8(n=64) | -18.4 (n=60) | -8.2 (n=33) | -9.3 (n=28) |
| LVEDD | -7.1 (n=62) | -4.8 (n=53) | -5.0 (n=27) | -2.5 (n=26) |
| LVESD | -5.4 (n=60) | -3.4 (n=53) | -5.1 (n=27) | -1.3 (n=26) |

- FDA Clinical Review

- Panel Presenation

**Notes:**
Therefore, the CorCap decreased LVEDV and LVESV in the Treatment arm when compared to the Control (the decrease was not statistically significant) and the largest difference in the noMVR group. Note that the largest reduction in LV mass index occurs in the MVR group and both Treatment and Control arms have similar reductions. Therefore, both decreases are clinically meaningful.  There was a higher improvement in sphericity in the Treatment group compared to Control; the changes are not clinically meaningful.  It is difficult to assess dimensions when using a mechanical constraint that could also change the shape of the ventricle.  The changes in these clinical surrogates did not translate into changes of functional capacity or mortality.  Although the Sponsor has presented data correlating cardiac structural changes to functional endpoints (see Sponsor panel pack), these data are difficult to interpret in light of the amount of missing data for CoreLab NYHA, Peak VO2 and QOL.

## Brain Natriuretic Peptide (BNP)

| Treatment |  | Control |  |
| --- | --- | --- | --- |
| # | Mean + SD | # | Mean + SD |
| 71 | 176.0 + 229.9 | 80 | 184.0 + 284.7 |
| 106 | 238.3 + 307.6 | 104 | 176.7 + 211.4 |

- FDA Clinical Review

- Panel Presenation

**Notes:**
The Sponsor has reported BNP as one of other secondary endpoints.  The BNP relates to intraventricular volume and pressure.  A rise in BNP is not desirable in an HF population, although values can vary with age, renal function, etc. Therapy that is directed at lowering filling pressures and volume as well as dimensions, should lower the BNP.  Values over 100 are considered HF related.
 There are a large amount of missing values for BNP.  Values at baseline and 6 mos are shown below for patients with data at 6 mos.

Therefore, although missing data and wide SD, the Treatment group tended to have BNP increase whereas the Control group decreased slightly. 

## Adverse Events Related to Hemodynamic Compromise

|  | Any Adverse Event |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Treatment (n=148) |  | Control (n=152) |  |  |
|  | # Pts | % of 148 | #Pts | % of 152 | p-value |
| Hemodynamic Compromise | 90 | 60.8 | 75 | 49.3 | 0.05 |

|  | Any Serious Adverse Event |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
|  | Treatment (n=148) |  | Control (n=152) |  |  |
|  | # Pts | % of 148 | #Pts | % of 152 | p-value |
| Hemodynamic Compromise | 90 | 60.8 | 74 | 48.7 | 0.14 |

- FDA Clinical Review

- Panel Presenation

**Notes:**
Constriction of the LV would impair filling and the use of the Frank Starling mechanism to improve cardiac output by increasing preload.  A constricted ventricle would not be able to absorb increases in end-diastolic volume and would therefore rely on inotropic and chronotropic reserve to augment output.  Such an early event could be captured in the amount of inotropes needed in the intensive care unit to respond to “hemodynamic compromise”. As per Sponsor’s submission, the following relates any AE and any Serious AE by treatment group.