Impella Ventricular Support Systems
Device Facts
| Record ID | P140003S018 |
|---|---|
| Device Name | Impella Ventricular Support Systems |
| Applicant | Abiomed, Inc. |
| Product Code | OZD · Cardiovascular |
| Decision Date | Feb 7, 2018 |
| Decision | APPR |
| Device Class | Class 3 |
| Attributes | Therapeutic, Real-World Evidence |
Real-World Evidence
| Submission | Device | Sponsor | RWD Sources | RWE Use Summary | Key Tags |
|---|---|---|---|---|---|
| P140003S018 · Feb 7, 2018 | Impella Ventricular Support Systems | Abiomed, Inc. | Impella Registry (retrospective, observational, multi-center); Published clinical literature | The Impella Registry provided retrospective, real-world data on 93 patients treated with Impella devices for cardiogenic shock in the setting of cardiomyopathy, myocarditis, or peripartum cardiomyopathy. This was supplemented by a literature review of clinical outcomes for similar patient populations to support the expansion of the device indication. | Retrospective registry; Real-world clinical data; Cardiogenic shock; Cardiomyopathy; Myocarditis; Peripartum cardiomyopathy |
Clinical Evidence
| Study Design | Population | Comparator | Key Endpoints |
|---|---|---|---|
| Impella Registry; Retrospective, observational, multi-center registry; Follow-up/Duration: Follow-up at discharge and 30 days; Study Period: Data collected through June 10, 2016 | 93 U.S. patients with ongoing cardiogenic shock in the setting of cardiomyopathy (n=50), myocarditis (n=34), or peripartum cardiomyopathy (n=9); Sample Size: 93; Number of Sites: 88 total participating sites (44 U.S. sites active as of 2016) | Not applicable for this study | Survival to discharge, myocardial recovery, survival to 30 days, hemodynamic improvement, and device/procedure-related adverse events |
| Literature Review of Mechanical Circulatory Support; Systematic literature review of case reports, single-center studies, and multi-center series | Patients with cardiogenic shock secondary to cardiomyopathy, myocarditis, or peripartum cardiomyopathy; Sample Size: Not specified (multiple studies); Number of Sites: Not applicable | Other mechanical circulatory support devices (ECMO, surgical VADs) | Survival to explant, survival to discharge, adverse event rates |
Indications for Use
The Impella 2.5, Impella CP, Impella 5.0, and Impella LD Catheters, in conjunction with the Automated Impella Controller, are temporary ventricular support devices intended for short term use (≤4 days for the Impella 2.5 and Impella CP, and ≤6 days for the Impella 5.0 and Impella LD) and indicated for the treatment of ongoing cardiogenic shock that occurs: - immediately (<48 hours) following acute myocardial infarction or open heart surgery, or - in the setting of cardiomyopathy, including peripartum cardiomyopathy, or myocarditis as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures.* The intent of the Impella Support Systems therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function. *Optimal medical management and conventional treatment measures include volume loading and use of pressors and inotropes, with or without IABP.
Device Story
Impella Ventricular Support Systems consist of micro-axial rotary blood pumps mounted on 9F drive catheters; connected to external Automatic Impella Controller (AIC). Pumps placed percutaneously (2.5, CP, 5.0) or surgically (LD) with inflow in left ventricle and outflow in ascending aorta. AIC powers motor, provides user interface, and manages purge fluid (dextrose/heparin) via disposable cassette to prevent blood ingress. Used in hospital settings (ICU, cath lab, OR) by trained professionals; portable for transport. Device draws blood from LV and expels into aorta to reduce ventricular work, increase cardiac index, and improve hemodynamics. Supports heart recovery or bridge to further therapy. Output monitored by clinicians to guide management; benefits include hemodynamic stabilization and potential survival to discharge.
Clinical Evidence
Retrospective observational analysis of 93 U.S. patients from the Impella Registry (50 cardiomyopathy, 34 myocarditis, 9 PPCM). Primary endpoints: survival to discharge, myocardial recovery, 30-day survival, hemodynamic improvement. Results: 58% survival to discharge/transfer; 67% of survivors achieved myocardial recovery. Hemodynamic improvements observed (p<0.05 for cardiac index, MAP, PCWP). Adverse events included acute renal dysfunction (35%), hemolysis (13%), and bleeding (10%). CEC adjudicated all deaths as not device-related. Literature review compared Impella outcomes favorably against ECMO and surgical VADs regarding morbidity rates.
Technological Characteristics
Micro-axial rotary blood pump; 9F drive catheter; 12F, 14F, or 21F pump diameters. Energy source: external AIC console. Connectivity: standalone, portable. Purge system: dextrose/heparin solution via disposable cassette. Placement: percutaneous (femoral/axillary) or surgical (aortic).
Indications for Use
Indicated for patients with ongoing cardiogenic shock (≤48 hours post-MI or surgery, or due to cardiomyopathy/myocarditis/peripartum cardiomyopathy) with isolated left ventricular failure unresponsive to optimal medical management. Contraindicated in patients with mural thrombus, mechanical aortic valve, aortic stenosis (≤0.6 cm²), moderate/severe aortic insufficiency, severe peripheral arterial disease, significant right heart failure, combined cardiorespiratory failure, septal defect, LV rupture, or cardiac tamponade.
Regulatory Classification
Identification
A blood pump that provides temporary full or partial left heart support
Reference Devices
- BVS/AB5000 VAD
- HeartMate II
- Impella RP
Submission Summary (Full Text)
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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)
## I. GENERAL INFORMATION
Device Generic Name: Temporary Ventricular Support Device
Device Trade Name: Impella Ventricular Support Systems
Device Procode: OZD
Applicant's Name and Address: Abiomed, Inc.
22 Cherry Hill Drive
Danvers, MA 01923
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P140003/S018
Date of FDA Notice of Approval: February 7, 2018
The original PMA for the Impella 2.5 System (PMA P140003) was approved on March 23, 2015. The approved indication for use for the Impella 2.5 System is:
*The Impella 2.5 System is a temporary (< 6 hours) ventricular support device indicated for use during high risk percutaneous coronary interventions (PCI) performed in elective or urgent, hemodynamically stable patients with severe coronary artery disease and depressed left ventricular ejection fraction, when a heart team, including a cardiac surgeon, has determined high risk PCI is the appropriate therapeutic option. Use of the Impella 2.5 in these patients may prevent hemodynamic instability which can result from repeat episodes of reversible myocardial ischemia that occur during planned temporary coronary occlusions and may reduce peri- and post-procedural adverse events.*
The SSED to support the indication is available on the CDRH website and is incorporated by reference here: https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140003B.pdf.
On April 7, 2016 panel-track supplements (P140003/S004 and P140003/S005) were approved for patients experiencing ongoing cardiogenic shock immediately (<48 hours) following acute myocardial infarction or open heart surgery for the Impella Ventricular Support Systems. The SSEDs to support these indications are available on the CDRH website at: https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140003S004B.pdf and https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140003S005B.pdf, respectively. The current supplement (P140003/S018) was submitted to expand this indication to incorporate the setting of cardiomyopathy, including peripartum cardiomyopathy or myocarditis within the ongoing cardiogenic shock indication.
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## II. INDICATIONS FOR USE
The Impella 2.5, Impella CP, Impella 5.0, and Impella LD Catheters, in conjunction with the Automated Impella Controller, are temporary ventricular support devices intended for short term use (≤4 days for the Impella 2.5 and Impella CP, and ≤6 days for the Impella 5.0 and Impella LD) and indicated for the treatment of ongoing cardiogenic shock that occurs:
- immediately (<48 hours) following acute myocardial infarction or open heart surgery, or
- in the setting of cardiomyopathy, including peripartum cardiomyopathy, or myocarditis
as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures.* The intent of the Impella Support Systems therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function.
*Optimal medical management and conventional treatment measures include volume loading and use of pressors and inotropes, with or without IABP.
### III. CONTRAINDICATIONS
The Impella Ventricular Support Systems are contraindicated for patients with the following conditions:
- Mural thrombus in the left ventricle
- Mechanical aortic valve or heart constrictive device
- Aortic valve stenosis/calcification (equivalent to an orifice area of 0.6 cm² or less)
- Moderate to severe aortic insufficiency (echocardiographic assessment graded as ≥ +2)
- Severe peripheral arterial disease that precludes the placement of an Impella Catheter
- Significant right heart failure
- Combined cardiorespiratory failure
- Presence of an atrial or ventricular septal defect (including post-infarct VSD)
- Left ventricular rupture
- Cardiac tamponade
### IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the Impella Ventricular Support Systems labeling.
### V. DEVICE DESCRIPTION
To accommodate a range of cardiac flow requirements and implant techniques, four different Impella support Catheters are available. Figure 1 shows general overall design for the Impella Catheters. All of the Impella Catheters consist of a micro-axial rotary
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blood pump mounted on a 9F drive catheter, which is connected to an external controller, the Automatic Impella Controller (AIC).
Figure 1: Impella ventricular support catheter design
There are four different Impella Catheters, as shown in Figure 2. The peripherally placed catheters are the Impella 2.5, the Impella CP and the Impella 5.0, which have blood pump diameters of 12F, 14F and 21F, respectively. In addition, a fourth 21F surgically placed Impella Catheter, the Impella LD is available.
Figure 2: The Impella Ventricular Support Catheters
The Impella Catheters shown above are all placed with the cannula inflow located in the left ventricle and the outflow located in the ascending aorta, as shown in Figure 3. Blood
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is drawn through the cannula situated in the left ventricle and expelled into the aorta. As shown in Figures 2 and 3, the three peripherally placed pumps (the Impella 2.5, Impella CP and Impella 5.0) have 6F pigtails attached to their tips, to enable device placement over the wire and positioning in the correct anatomical position. When placing an Impella Catheter peripherally (via a guidewire), the device is loaded over the wire through the pigtail. The Impella 5.0, while placed peripherally, requires a graft and a surgical cut-down and can access the circulation through either the femoral or axillary artery. Alternatively, the Impella LD is surgically placed directly through the aorta into the heart (see Figure 3).
Figure 3: Ventricular placement of the Impella Catheters
The Impella Catheters are operated by the same external drive console, the Automatic Impella Controller (AIC), shown in Figure 4. The AIC generates signals required to power the drive motor of the Impella Catheters and provides a user interface. The AIC also incorporates the disposable Impella Purge Cassette system, which provides a fluid pressure barrier to prevent blood from entering the Impella Catheter's drive motor. A dextrose (5-40% with 50 Units/ml of heparin added) solution is used as a purge fluid. The AIC is portable and can be used for patient transport by trained healthcare professionals within healthcare facilities and during medical transport between hospitals (i.e., ambulance, helicopter or fixed-wing aircraft).
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Figure 4: The AIC with an Impella Catheter and its Impella Purge Cassette
Additional sterile, disposable implant accessories are provided with the Impella Catheters to assist in their percutaneous insertion. For the Impella 2.5, these components are a 13F peel-away introducer kit (manufactured by Merit Medical) and a 0.018" placement guidewire (manufactured by Lake Region Medical). The Impella CP accessories are a 14F peel-away introducer kit (manufactured by Oscor Medical) and the identical placement guidewire packaged with the Impella 2.5. The Impella 5.0 is packaged with a 23F peel-away introducer kit (manufactured by Oscor Medical), a 0.018" guidewire (manufactured by Lake Region Medical) and a surgical clamp to assist in hemostasis.
A reusable cart for the AIC is also provided for ease of patient transport within the hospital.
## VI. ALTERNATIVE PRACTICES AND PROCEDURES
There are several other alternatives for the treatment of ongoing cardiogenic shock. These alternatives include inotropic support, intra-aortic balloon pump (IABP) counterpulsation therapy, and surgical left ventricular assist devices. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.
## VII. MARKETING HISTORY
The Impella pumps have received CE mark in the European Union as well as approval in Canada to treat all patients with reduced left ventricular function, including those in cardiogenic shock (of any origin). Neither the AIC nor any of the Impella support
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catheters have been withdrawn from marketing for any reason related to their safety or effectiveness.
### VIII. PROBABLE ADVERSE EFFECTS OF THE DEVICE ON HEALTH
Below is a list of the probable adverse effects (e.g., complications) associated with the use of the device.
- Acute renal dysfunction
- Aortic insufficiency
- Aortic valve injury
- Atrial fibrillation
- Bleeding
- Cardiogenic shock
- Cardiac tamponade
- Cardiopulmonary resuscitation
- Cerebral vascular accident/Stroke
- Death
- Device malfunction
- Failure to achieve angiographic success
- Hemolysis
- Hepatic failure
- Insertion site infection
- Limb ischemia
- Myocardial infarction
- Need for cardiac, thoracic or abdominal operation
- Perforation
- Renal failure
- Repeat revascularization
- Respiratory dysfunction
- Sepsis
- Severe hypotension
- Thrombocytopenia
- Thrombotic vascular (non-CNS) complication
- Transient ischemic attack
- Vascular injury
- Ventricular arrhythmia, fibrillation or tachycardia
For the specific adverse events that occurred in the clinical study, please see Section X below.
### IX. SUMMARY OF NONCLINICAL STUDIES
Preclinical testing was conducted on the Impella 2.5 Catheter, the AIC, and the Impella Purge Cassette in support of P140003 and summaries can be found in the original SSED, here: http://www.accessdata.fda.gov/cdrh_docs/pdf14/P140003b.pdf. The testing to support the increased duration of use for the ongoing cardiogenic shock indication (the original indication was for < 6 hours, while the ongoing cardiogenic shock indication is for 4-6 days) and to support the additional Impella Catheters (Impella CP, Impella 5.0, and Impella LD) can be found in the P140003/S004 and P140003/S005 SSED, here https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140003S004B.pdf and https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140003S005B.pdf, respectively.
### X. SUMMARY OF PRIMARY CLINICAL STUDIES
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The applicant performed an analysis of real-world, use data captured in the Impella Registry to establish a reasonable assurance of safety and effectiveness in the treatment of patients suffering from cardiomyopathy, myocarditis, or peripartum cardiomyopathy with ongoing cardiogenic shock with the Impella Ventricular Support Systems. Additionally, a detailed literature review of the treatment outcomes for the new patient group was used to further support the overall safety and effectiveness of the Impella devices in the new patient group. Data from the Impella Registry and the literature review were the basis for the PMA approval decision. A summary of the clinical study and literature review are presented below.
### A. Study Design
The Impella Registry is an ongoing, multi-center, retrospective, observational registry for collection of de-identified data for patients treated with the Impella 2.5, Impella CP, Impella 5.0, Impella LD and Impella RP Support Systems. The registry, which was started by ABIOMED in 2009, is open for participation by qualifying sites in the U.S., Canada and Europe. A total of 88 sites have participated in the registry since its initiation. As of December 31, 2016, there were 58 open sites of which 44 were U.S. sites. All patients identified for this analysis were U.S. patients. The sites include high and low volume centers, academic (teaching) and non-academic hospitals, public and private institutions as well as for profit and not for profit centers, almost entirely from the United States. Data are collected at all participating sites retrospectively without pre-selection of patients, and include cardiomyopathy, myocarditis, and peripartum cardiomyopathy (PPCM) patients treated with the Impella 2.5, Impella CP and Impella 5.0/LD Systems.
The data collection from the Impella Registry includes IRB approval, complete data monitoring, adverse events (AEs) monitoring, and CEC adjudication of major AEs. All data are entered electronically by the sites. The time during which the Impella Registry data were collected is shown in Figure 5. Eligible patients were those who were reported in the Impella Registry as having presented with ongoing cardiogenic shock in the setting of cardiomyopathy, myocarditis, or peripartum cardiomyopathy, and required mechanical circulatory support with Impella devices, through June 10, 2016.
Figure 5: Time intervals for Impella implants data collection by type of device
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The database for this Panel Track Supplement included 93 patients treated with an Impella Ventricular Support System. These included 50 patients with cardiomyopathy (4 Impella 2.5, 29 Impella CP, and 17 Impella 5.0), 34 patients with myocarditis (14 Impella 2.5, 12 Impella CP and 8 Impella 5.0), and 9 patients with PPCM (5 Impella 2.5, 2 Impella CP and 2 Impella 5.0). The cardiomyopathy patients included the 50 most recent consecutive cardiomyopathy with ongoing cardiogenic shock patients enrolled in the Impella Registry. The patients with myocarditis and PPCM included all such patients enrolled in the Impella Registry.
#### 1. Clinical Inclusion and Exclusion Criteria
Eligible patients were those who were reported in the Impella Registry as having presented with ongoing cardiogenic shock in the setting of cardiomyopathy, myocarditis, or peripartum cardiomyopathy. They were deemed as requiring mechanical circulatory support and were treated off-label with the Impella devices based on the clinical judgement of their treating physician.
#### 2. Follow-up Schedule
All patients were followed post implantation according to their local standards of care. The Impella Registry collects follow-up data at discharge and 30 days.
#### 3. Clinical Endpoints
Data entered into the Impella Registry were collected electronically through standardized data collection forms. The endpoints analyzed in this application included: survival to discharge, myocardial recovery, survival to 30 days post Impella implant, hemodynamic improvement, and device-related and procedure-related adverse events. The analyses in this application focused on the discharge and 30-day post-implant time points.
### **B. Accountability of PMA Cohort**
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At the time of database extract, 93 patients were available for analysis . The number of patients in each analysis population for each Impella device is shown in Table 1.
Table 1: Analysis Populations
| Analysis Population | Total Cases | Impella 2.5 | Impella CP | Impella 5.0 | Impella LD |
| --- | --- | --- | --- | --- | --- |
| All Subjects | 93 | 23 | 43 | 27 | 0 |
| Cardiomyopathy | 50 | 4 | 29 | 17 | 0 |
| Myocarditis | 34 | 14 | 12 | 8 | 0 |
| Peripartum Cardiomyopathy | 9 | 5 | 2 | 2 | 0 |
### C. Study Population Demographics and Baseline Parameters
The demographics and baseline characteristics of all the cardiomyopathy, myocarditis and PPCM patients are shown below in Table 2 and 3. Ninety-two of the 93 patients were in cardiogenic shock at the time of Impella implant. One of the PPCM patients was not in cardiogenic shock at the time of Impella implant and the device was implanted to improve left ventricular function and prevent further hemodynamic deterioration.
Table 2: Demographics and baseline characteristics
| Parameter | All Subjects (N=93) | Cardiomyopathy (N=50) | Myocarditis (N=34) | Peripartum Cardiomyopathy (N=9) |
| --- | --- | --- | --- | --- |
| Age, years (mean +/- SD) | 48 +/- 17 | 55 +/- 12 | 42 +/- 17 | 27 +/- 8 |
| Male, % (N) | 59% (55) | 76% (38) | 50% (17) | 0% (0) |
| Left ventricular ejection fraction (LVEF), % (mean +/- SD) (N) | 16% +/- 8% (77) | 15% +/- 6 (39) | 18% +/- 10 (29) | 17% +/- 7 (9) |
| Number of inotropes at baseline (mean +/- SD) | 2 +/- 1 | 3 +/- 1 | 2 +/- 1 | 2 +/- 1 |
| Diabetes, % (N) | 28% (26) | 44% (22) | 9% (3) | 11% (1) |
| Smoking, % (N) | 26% (24) | 22% (11) | 33% (11) | 22% (2) |
| Hypertension, % (N) | 53% (49) | 62% (31) | 44% (15) | 33% (3) |
| Arrhythmia, % (N) | 39% (36) | 56% (28) | 21% (7) | 11% (1) |
| Congestive heart failure, % (N) | 59% (54) | 88% (44) | 26% (9) | 13% (1 of 8) |
| NYHA III/IV, % (N) | 95% (41 of 43) | 100% (28 of 28) | 83% (10 of 12) | 100% (3 of 3) |
| Renal insufficiency | 33% (30) | 54% (26) | 12% (4) | 0% (0) |
| Known history of cardiomyopathy, % (N) | 52% (47) | 82% (41) | 15% (5 of 33) | 13% (1 of 8) |
| Prior myocardial infarction, % (N) | 11% (10) | 18% (9) | 3% (1) | 0% (0) |
| Prior AICD/pacer, % (N) | 33% (31) | 54% (27) | 9% (3) | 11% (1) |
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Table 3: Baseline hemodynamics
| Parameter | All Subjects (N=93) | Cardio- myopathy (N=50) | Myocarditis (N=34) | Peripartum Cardiomyopathy (N=9) |
| --- | --- | --- | --- | --- |
| Cardiac index (L/min/m²) Mean +/- SD (N) | 1.97 +/- 0.74 (48) | 1.98 +/- 0.76 (20) | 1.82 +/- 0.46 (23) | 2.60 +/- 1.37 (5) |
| Heart rate (bpm) Mean +/- SD (N) | 104.5 +/- 27.8 (89) | 102.0 +/- 27.8 (48) | 107.8 +/- 28.0 (32) | 106.2 +/- 28.8 (9) |
| Systolic arterial pressure (mmHg) Mean +/- SD (N) | 98.0 +/- 20.9 (90) | 95.5 +/- 20.2 (48) | 100.4 +/- 21.5 (33) | 102.8 +/- 22.2 (9) |
| Diastolic arterial pressure (mmHg) Mean +/- SD (N) | 65.7 +/- 15.2 (90) | 65.2 +/- 16.4 (48) | 66.1 +/- 13.7 (33) | 66.5 +/- 16.1 (9) |
| Mean arterial pressure (mmHg) Mean +/- SD (N) | 76.3 +/- 16.4 (90) | 74.3 +/- 17.3 (48) | 78.3 +/- 15.2 (33) | 79.9 +/- 16.2 (9) |
| Pulmonary capillary wedge pressure (mmHg) Mean +/- SD (N) | 25.9 +/- 9.8 (35) | 27.9 +/- 14.0 (13) | 25.2 +/- 6.6 (20) | 21.5 +/- 3.5 (2) |
| Central venous pressure (mmHg) Mean +/- SD (N) | 24.6 +/- 5.1 (7) | 27.5 +/- 9.2 (2) | 22.3 +/- 2.6 (4) | 28.0 (1) |
Additionally, Impella support characteristics are provided below (Table 4). Impella CP was the most used device (46%), followed by Impella 5.0 (29%) and Impella 2.5 (25%). Femoral access site was predominantly used (70%). Mean duration of support was 123 +/- 200 hours (5±8 days) for the full cohort. For the full patient cohort, the 90th percentile of support duration was 120 hours (5 days), 233 hours (9.7 days), and 384 hours (16 days) for patients supported with the Impella 2.5, Impella CP, and Impella 5.0, respectively.
Table 4: Impella support characteristics
| Parameter | All Subjects (N=93) | Cardio- myopathy (N=50) | Myocarditis (N=34) | Peripartum Cardiomyopathy (N=9) |
| --- | --- | --- | --- | --- |
| Impella device type (first device) | | | | |
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| Parameter | All Subjects (N=93) | Cardio- myopathy (N=50) | Myocarditis (N=34) | Peripartum Cardiomyopathy (N=9) |
| --- | --- | --- | --- | --- |
| Impella 2.5, % (N) | 25% (23) | 8% (4) | 41% (14) | 56% (5) |
| Impella CP, % (N) | 46% (43) | 58% (29) | 35% (12) | 22% (2) |
| Impella 5.0, % (N) | 29% (27) | 34% (17) | 24% (8) | 22% (2) |
| Impella access (% femoral), % (N) | 70% (65) | 64% (32) | 79% (27) | 75% (6) |
| Duration of device support, hours (mean +/- SD) (N) | 123 +/- 200 (80) | 115 +/- 101 (46) | 91 +/- 74 (28) | 338 +/- 670 (6) |
| 90^{th} percentile of support duration | | | | |
| Impella 2.5, hours | 120 | 78 | 72 | 120 |
| Impella CP, hours | 233 | 233 | 72 | 241 |
| Impella 5.0, hours | 384 | 384 | 1704 | 216 |
#### D. Safety and Effectiveness Results
Outcomes were defined as survival to discharge and survival to 30 days after device implant. Survival to discharge and patient cardiac status at discharge for the full patient cohort, and all three cohorts separately, are shown in Figures 6-9.
For the full patient cohort, 54 patients (58%) were either discharged alive (N=43, 46%) or transferred on Impella support to another medical facility for escalation of care (N=11, 12%); 39 (42%) expired during index hospitalization (Figure 6A). Of the 43 patients discharged alive, 29 recovered their cardiac function (67% of the discharged patients), 10 received a durable VAD (23% of the discharged patients), and 4 received a heart transplant (9% of the discharged patients) (Figure 6B).
Figure 6: Survival to discharge (A) and patient status at discharge (B) – All patients (N=93)
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For the cardiomyopathy patients, 25 patients were either discharged alive (N=22, 44%) or transferred on Impella support to another medical facility for escalation of care (N=3, 6%); 25 (50%) expired during index hospitalization (Figure 7A). Of the 22 patients discharged alive, 10 recovered their cardiac function, 9 received a durable VAD, and 3 received a heart transplant (Figure 7B).
Figure 7: Survival to discharge (A) and patient status at discharge (B) – Cardiomyopathy patients (N=50)
For the myocarditis patients, 21 patients were either discharged alive (N=16, 47%) or transferred on Impella support to another medical facility for escalation of care (N=5, 15%); 13 (38%) expired during index hospitalization (Figure 8A). Of the 16 patients
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discharged alive, 15 recovered their cardiac function and one received a heart transplant (Figure 8B).
Figure 8: Survival to discharge (A) and patient status at discharge (B) – Myocarditis patients (N=34)
For the PPCM patients, 8 patients were either discharged alive (N=5, 56%) or transferred on Impella support to another medical facility for escalation of care (N=3,
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33%); one (11%) expired during index hospitalization (Figure 9A). Of the 5 patients discharged alive, 4 recovered their cardiac function and one received a durable left ventricular assist device (Figure 9B).
Figure 9: Survival to discharge (A) and patient status at discharge (B) – PPCM patients (N=9)
# Patient Hemodynamics
Hemodynamic parameters on Impella support compared to baseline are shown in Table 5. Impella support increased cardiac index and systolic, diastolic, and mean arterial blood pressure, and reduced pulmonary capillary wedge pressure, consistent with previous reports.
Table 5: Comparison of hemodynamics pre-support and on-support (paired data)
| Parameter | Pre-Support (N=93) | On-Support (N=93) | P-value |
| --- | --- | --- | --- |
| Cardiac index (L/min/m²) Mean +/- SD (N) | 1.93+/- 0.51 (25) | 2.27 +/- 0.83 (25) | 0.05 |
| Heart rate (bpm) Mean +/- SD (N) | 104.8+/- 28.7 (75) | 110.6 +/- 41.5 (75) | 0.24 |
| Systolic arterial pressure (mmHg) Mean +/- SD (N) | 97.5 +/- 18.8 (71) | 104.4 +/- 23.0 (71) | 0.02 |
| Diastolic arterial pressure (mmHg) Mean +/- SD (N) | 65.2 +/- 13.8 (70) | 70.8 +/- 18.4 (70) | 0.04 |
| Mean arterial pressure (mmHg) Mean +/- SD (N) | 75.5 +/- 15.0 (72) | 83.1 +/- 18.4 (72) | 0.003 |
| Pulmonary capillary wedge pressure (mmHg) | 23.5 +/- 7.3 (14) | 18.7 +/- 6.7 (14) | 0.02 |
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| Parameter | Pre-Support (N=93) | On-Support (N=93) | P-value |
| --- | --- | --- | --- |
| Mean +/- SD (N) | | | |
| Central venous pressure (mmHg) Mean +/- SD (N) | 24.6 +/- 6.2 (5) | 19.5 +/- 10.4 (5) | 0.34 |
### In-Hospital Adverse Events
Site-reported in-hospital adverse events are shown in Table 6. There were no valve injuries or valve dysfunction adverse events reported. The major complications reported for the full cohort included cerebrovascular accident (4%), acute renal dysfunction (35%), acute hepatic failure (5%), hemolysis (13%), bleeding requiring transfusion (10%), anemia requiring transfusion (11%), infection (13%), limb ischemia (4%), vascular complication with (3%) or without (4%) surgery, respiratory dysfunction/failure (4%), and ventricular arrhythmia (9%). Based on the site-reported data (local PI assessment of event causality), only a fraction of these rates were attributed to the Impella device and the events resolved without residual effect in most of the cases, unless the event of death occurred. Overall, the results did not show any evidence of increased morbidity associated with the Impella support in cardiomyopathy, myocarditis, and PPCM patients.
Table 6: Site-reported adverse events (to discharge)
| In-Hospital Adverse Events | All Subjects (N=93) | Cardiomyopathy (N=50) | Myocarditis (N=34) | Peripartum Cardiomyopathy (N=9) |
| --- | --- | --- | --- | --- |
| Death | 42% (39/93) | 50% (25/50) | 38% (13/34) | 11% (1/9) |
| Cerebrovascular Accident (CVA)/Stroke | 4% (4/93) | 4% (2/50) | 6% (2/34) | 0% (0/9) |
| Transient Ischemic Attack (TIA) | 0% (0/93) | 0% (0/50) | 0% (0/34) | 0% (0/9) |
| Acute Renal Dysfunction/Failure | 35% (33/93) | 30% (15/50) | 47% (16/34) | 22% (2/9) |
| Acute Hepatic Failure | 5% (5/93) | 6% (3/50) | 6% (2/34) | 0% (0/9) |
| Hemolysis | 13% (12/93) | 16% (8/50) | 12% (4/34) | 0% (0/9) |
| Valve Injury (Any Valve) | 0% (0/93) | 0% (0/50) | 0% (0/34) | 0% (0/9) |
| Anemia Requiring Transfusion | 11% (10/93) | 2% (1/50) | 18% (6/34) | 33% (3/9) |
| Bleeding Requiring Transfusion | 10% (9/93) | 2% (1/50) | 21% (7/34) | 11% (1/9) |
| Infection | 13% (12/93) | 12% (6/50) | 9% (3/34) | 33% (3/9) |
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| In-Hospital Adverse Events | All Subjects (N=93) | Cardiomyopathy (N=50) | Myocarditis (N=34) | Peripartum Cardiomyopathy (N=9) |
| --- | --- | --- | --- | --- |
| Limb Ischemia | 4% (4/93) | 0% (0/50) | 9% (3/34) | 11% (1/9) |
| Vascular Complication Requiring Surgery | 3% (3/93) | 2% (1/50) | 3% (1/34) | 11% (1/9) |
| Vascular Complication Without Surgery | 4% (4/93) | 4% (2/50) | 3% (1/34) | 11% (1/9) |
| Respiratory Dysfunction/Failure | 4% (4/93) | 2% (1/50) | 6% (2/34) | 11% (1/9) |
| Ventricular Arrhythmia | 9% (8/93) | 2% (1/50) | 15% (5/34) | 22% (2/9) |
There were 39 in-hospital deaths (42%). The causes of death for each subgroup are categorized in Table 7. The majority of the deaths (N=25, 64%) were attributed to heart failure or cardiogenic shock.
Table 7: Causes of in-hospital death
| Cause of Death | Impella Registry Population | | |
| --- | --- | --- | --- |
| | Cardiomyopathy (N=50) | Myocarditis (N=34) | Peripartum Cardiomyopathy (N=9) |
| Heart Failure or Cardiogenic Shock | 30% (15) | 26.47% (9) | 11.11% (1) |
| Myocardial Infarction | 4% (2) | 0 | 0 |
| CVA/Stroke | 0 | 2.94% (1) | 0 |
| Procedural Complication | 0 | 2.94% (1) | 0 |
| Heart Failure with MSOF | 16% (8) | 2.94% (1) | 0 |
| Unknown | 0 | 2.94% (1) | 0 |
| **Total** | **50% (25)** | **38.23% (13)** | **11.11% (1)** |
CVA – cerebrovascular accident; MSOF – multi-system organ failure
#### Relatedness to the Device and Procedure
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The Clinical Events Committee (CEC) determined the potential relationship to the device (Table 8) and procedure (Table 9) for each death. All deaths were adjudicated by the CEC as not related to the Impella device.
Two deaths in the myocarditis cohort were adjudicated by the CEC as probably related to the procedure. One myocarditis patient underwent an endomyocardial biopsy complicated by perforation of the inferior free wall of the right ventricle leading to cardiac tamponade and requiring emergent mediastinal exploration to suture the laceration and stop the bleeding. The patient expired four days later during the index hospitalization, and this death was adjudicated as probably related to the endomyocardial biopsy procedure. A second myocarditis patient was supported initially with an Impella CP but did not significantly improve. Consequently, the patient was escalated to an AB5000 LVAD. While on LVAD support, the patient developed multiple complications and support was withdrawn upon the request from the patient's family. This death was adjudicated as probably related to the LVAD implant procedure.
Table 8: In-hospital deaths CEC-adjudicated as related to the device
| Deaths: CEC Device Relatedness | Definite | Probable | Possible | Remote | Not-Related | Unknown | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Cardiomyopathy | 0 | 0 | 0 | 0 | 25 | 0 | 25 |
| Myocarditis | 0 | 0 | 0 | 0 | 13 | 0 | 13 |
| PPCM | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
Table 9: In-hospital deaths CEC-adjudicated as related to the procedure
| Deaths: CEC Procedure Relatedness | Definite | Probable | Possible | Remote | Not-Related | Unknown | Total |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Cardiomyopathy | 0 | 0 | 0 | 0 | 25 | 0 | 25 |
| Myocarditis | 0 | 2 | 0 | 0 | 11 | 0 | 13 |
| PPCM | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
# Patient Survival at 30 Days
The overall results (Kaplan-Meier curve estimates) for 30-day survival for the patients are shown in Figure 10 (full patient cohort), Figure 11 (cardiomyopathy patients), Figure 12 (myocarditis patients), and Figure 13 (PPCM patients). Overall outcome results appear favorable for this sick patient group, particularly when compared to the published results for similar patients (see the supplemental clinical information section below).
Figure 10: Kaplan-Meier curve estimates for 30-day survival – all patients (N=93)
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Figure 11: Kaplan-Meier curve estimates for 30-day survival – cardiomyopathy patients (N=50)
Figure 12: Kaplan-Meier curve estimates for 30-day survival – myocarditis patients (N=34)
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Figure 13: Kaplan-Meier curve estimates for 30-day survival – PPCM patients (N=9)
# Device Failures and Replacements
There was one device failure reported during the study. One myocarditis patient experienced device failure after 12 days on support. The device was explanted without clinical sequelae. No device failures were reported for the cardiomyopathy or PPCM patients. One cardiomyopathy patient underwent a device replacement after the initial device migrated and could not be repositioned across the aortic valve.
# 3. Pediatric Extrapolation
In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.
# XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION
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The applicant conducted a comprehensive literature review on the use of mechanical circulatory support in the setting of cardiogenic shock secondary to cardiomyopathy, myocarditis, or PPCM, to further enhance the body of evidence from the Impella Registry supporting the reasonable assurance of safety and effectiveness for the Impella family of devices. The literature review includes two parts: 1) a review of the literature for Impella use in the above setting, along with the FDA approved AB/BVS5000 VAD use in the same setting; and 2) a review of the literature for the use of other mechanical circulatory support devices in the same setting.
### 1. Impella
The Impella review yielded 31 publications on the use of Impella devices for hemodynamic support in the setting of cardiomyopathy (16 publications) (1-16), myocarditis (13 publications) (8,17-28), or PPCM (3 publications) (29-31). The publications were either case reports on single patients (21 publications), single-center studies on hemodynamic support using Impella in the setting of cardiogenic shock where one or more of the patients presented with cardiomyopathy or myocarditis as the underlying cause (10 publications), or multi-center series on the use of Impella devices specifically for cardiomyopathy with ongoing cardiogenic shock (1 publication). For the cardiomyopathy patients, survival to explant was 72% (78 of 109). Ten of the reported cardiomyopathy patients were also included in the Impella Registry cohort. For the myocarditis patients, survival to explant was 71% (10 of 14 patients). One of the reported myocarditis patients was also included in the Impella Registry cohort. For the PPCM patients, recovery and survival to explant was 100% (3 patients).
### 2. Surgical VAD
The BVS/AB5000 review yielded only one publication, a retrospective multi-center study using data collected in the ABIOMED voluntary registry, on 11 patients supported with the BVS 5000 for cardiogenic shock secondary to acute myocarditis. The BVS/AB5000 System is the only FDA-approved system for use in patients suffering from acute cardiac disorders such as viral myocarditis. Survival to explant was 82%, with high rates of bleeding (73%), stroke (27%) and infection (18%).
### 3. Other Mechanical Support Devices
The review on the use of other MCS devices in cardiomyopathy or myocarditis yielded 18 retrospective single-center (n=16) or multi-center (n=2) studies on patients who required mechanical circulatory support due to cardiogenic shock in the setting of cardiomyopathy (32-40) or myocarditis (41-49) (910 patients total). Most studies reported the use of Extracorporeal Membrane Oxygenation (ECMO) only (10 of 18 studies). Survival to discharge ranged from 49% to 96%. For ECMO, the most widely reported support modality, survival to discharge ranged from 54% to 72%. Many of these articles did not report adverse events. When reported, the rates of stroke, bleeding, and infection were consistently higher in all other MCS devices than in
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Impella. The rates of limb ischemia were comparable. Hemolysis rate was absent in these data except for one non-Impella study.
The review on the use of other MCS devices in PPCM yielded one prospective multi-center study on patients who required VAD implant secondary to PPCM, using the INTERMACS registry (50). Survival to 1 month was 97%. Of note, only 66% of the patients described in the article above were in cardiogenic shock (INTERMACS 1 or 2) at the time of MCS device implant.
In conclusion, for available data on both Impella in these populations and other devices (pulsatile VADs and ECMO) the survival rates are comparable to the survival rates reported in the Impella Registry analyses (Figure 13). In addition for those articles where AEs were reported, the Impella Registry shows lower rates of morbidities associated with Impella than ECMO and surgical VADs. This is attributed to the relative low profile of Impella as a percutaneous device in this setting.
Figure 13: Survival comparisons of Impella Registry data, Impella literature, and other MCS reviewed in literature review
# XII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION
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In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Circulatory System Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.
### XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
#### A. Effectiveness Conclusions
In the population of patients experiencing ongoing cardiogenic shock in the setting of cardiomyopathy, myocarditis, or peripartum cardiomyopathy, the primary outcomes of interest are survival and myocardial recovery. In the Impella Registry Study, 50% of the cardiomyopathy patients were either discharged alive (44%) or transferred on Impella support (6%); 62% of the myocarditis patients were either discharged alive (47%) or transferred on Impella support (15%); and 89% of the PPCM patients were either discharged alive (56%) or transferred on Impella support (33%). The 30-day survival rates were 49% in cardiomyopathy, 63% in myocarditis, and 100% in PPCM. For the full cohort, for those patients who were discharged alive, 67% of the patients experienced myocardial recovery (29 of 43 patients).
Additionally, the Impella Registry Study showed improvement in hemodynamic status (including cardiac index; systolic, diastolic, and mean arterial blood pressure; and pulmonary capillary wedge pressure) from baseline to on-support.
In conclusion, given the totality of the information available for the Impella Ventricular Support Systems, the data demonstrate a beneficial therapeutic effect in patients experiencing ongoing cardiogenic shock in the setting of cardiomyopathy, myocarditis, or peripartum cardiomyopathy.
#### B. Safety Conclusions
The risks of the device are based on data collected in the Impella Registry as described above. There were no device-related serious adverse events in the Impella Registry Study. The safety profile of the Impella devices was favorable when compared with published results for the BVS/AB5000 surgical VAD, the only FDA approved system for use in patients suffering from acute cardiac disorders such as viral myocarditis, and with published results for other mechanical circulatory devices when used in similar patients.
#### C. Benefit-Risk Determination
The probable benefits of the device included potential survival to discharge and improved hemodynamic support.
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The probable risks of the device in patients who were suffering from ongoing cardiogenic shock in the setting of cardiomyopathy, including peripartum cardiomyopathy, and myocarditis were evaluated using the Impella Registry Study. The safety profile was comparable to that of the BVS/AB5000 surgical VAD and other mechanical circulatory support devices.
The benefit-risk evaluation is favorable for use of the Impella 2.5, Impella CP and Impella 5.0/LD as temporary ventricular support devices to support hemodynamics and augment the circulation in patients who are suffering from ongoing acute cardiogenic shock in the setting of cardiomyopathy, including peripartum cardiomyopathy, or myocarditis, where other standard therapies (pressors, inotropes, IABP) have failed.
1. Patient Perspectives
This submission did not include specific information on patient perspectives for this device.
In conclusion, given the available information above, the data support that for short term use (≤4 days for the Impella 2.5 and Impella CP, and ≤6 days for the Impella 5.0 and Impella LD) for the treatment of ongoing cardiogenic shock that occurs:
• immediately (<48 hours) following acute myocardial infarction or open heart surgery, or
• in the setting of cardiomyopathy, including peripartum cardiomyopathy, or myocarditis
as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures, the probable benefits outweigh the probable risks.
D. Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of the Impella Ventricular Support Systems for patients who are experiencing ongoing cardiogenic shock in the setting of cardiomyopathy, myocarditis, or peripartum cardiomyopathy.
XIV. CDRH DECISION
CDRH issued an approval order on February 7, 2018.
The applicant's manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).
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## **XV. APPROVAL SPECIFICATIONS**
Directions for use: See device labeling.
Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.
Post-approval Requirements and Restrictions: See approval order.
## **XVI. REFERENCES**
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4. 30. Schroeter MR, Unsold B, Holke K, Schillinger W. Pro-thrombotic condition in a woman with peripartum cardiomyopathy treated with bromocriptine and an Impella LP 2.5 heart pump. *Clinical research in cardiology : official journal of the German Cardiac Society* 2013;102:155-7.
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9. 35. den Uil CA, Galli G, Jewbali LS et al. First-Line Support by Intra-Aortic Balloon Pump in Non-Ischaemic Cardiogenic Shock in the Era of Modern Ventricular Assist Devices. *Cardiology* 2017;138:1-8.
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3. 38. Takayama H, Soni L, Kalesan B et al. Bridge-to-decision therapy with a continuous-flow external ventricular assist device in refractory cardiogenic shock of various causes. *Circ Heart Fail* 2014;7:799-806.
4. 39. Tarzia V, Bortolussi G, Bianco R et al. Extracorporeal life support in cardiogenic shock: Impact of acute versus chronic etiology on outcome. *J Thorac Cardiovasc Surg* 2015;150:333-40.
5. 40. Zeriouh M, Mohite P, Raj B et al. Short-term ventricular assist device as a bridge to decision in cardiogenic shock: is it a justified strategy? *The International journal of artificial organs* 2016;39:0.
6. 41. Atluri P, Ullery BW, MacArthur JW et al. Rapid onset of fulminant myocarditis portends a favourable prognosis and the ability to bridge mechanical circulatory support to recovery. *Eur J Cardiothorac Surg* 2013;43:379-82.
7. 42. Diddle JW, Almodovar MC, Rajagopal SK, Rycus PT, Thiagarajan RR. Extracorporeal membrane oxygenation for the support of adults with acute myocarditis. *Crit Care Med* 2015;43:1016-25.
8. 43. Hsu KH, Chi NH, Yu HY et al. Extracorporeal membranous oxygenation support for acute fulminant myocarditis: analysis of a single center's experience. *Eur J Cardiothorac Surg* 2011;40:682-8.
9. 44. Lorusso R, Centofanti P, Gelsomino S et al. Venoarterial Extracorporeal Membrane Oxygenation for Acute Fulminant Myocarditis in Adult Patients: A 5-Year Multi-Institutional Experience. *Ann Thorac Surg* 2016;101:919-26.
10. 45. Mirabel M, Luyt CE, Leprince P et al. Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support. *Crit Care Med* 2011;39:1029-35.
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46. Mody KP, Takayama H, Landes E et al. Acute mechanical circulatory support for fulminant myocarditis complicated by cardiogenic shock. J Cardiovasc Transl Res 2014;7:156-64.
47. Nakamura T, Ishida K, Taniguchi Y et al. Prognosis of patients with fulminant myocarditis managed by peripheral venoarterial extracorporeal membranous oxygenation support: a retrospective single-center study. J Intensive Care 2015;3:5.
48. Pages ON, Aubert S, Combes A et al. Paracorporeal pulsatile biventricular assist device versus extracorporeal membrane oxygenation-extracorporeal life support in adult fulminant myocarditis. J Thorac Cardiovasc Surg 2009;137:194-7.
49. Ting M, Wang CH, Tsao CI et al. Heart Transplantation Under Mechanical Circulatory Support for Acute Fulminant Myocarditis With Cardiogenic Shock: 10 Years' Experience of a Single Center. Transplantation proceedings 2016;48:951-5.
50. Loyaga-Rendon RY, Pamboukian SV, Tallaj JA et al. Outcomes of patients with peripartum cardiomyopathy who received mechanical circulatory support. Data from the Interagency Registry for Mechanically Assisted Circulatory Support. Circ Heart Fail 2014;7:300-9.
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