← Product Code [NPT](/productcode/NPT) · P130021S002

# MEDTRONIC COREVALVE SYSTEM (P130021S002)

_Medtronic, Inc. · NPT · Jun 12, 2014 · Cardiovascular · APPR_

**Canonical URL:** https://fda-staging.innolitics.com/device/P130021S002

## Device Facts

- **Applicant:** Medtronic, Inc.
- **Product Code:** [NPT](/productcode/NPT.md)
- **Decision Date:** Jun 12, 2014
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Cardiovascular
- **Attributes:** Therapeutic, Expedited Review

## Indications for Use

The Medtronic CoreValve™ system is indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis (aortic valve area ≤1.0 cm² or aortic valve area index ≤0.6 cm²/m², a mean aortic valve gradient of ≥40 mm Hg, or a peak aortic-jet velocity of ≥4.0 m/s) and with native anatomy appropriate for the 23, 26, 29, or 31 mm valve system who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., Society of Thoracic Surgeons operative risk score ≥8% or at a ≥15% risk of mortality at 30 days).

## Device Story

Transcatheter aortic valve replacement (TAVR) system; replaces native aortic valve without open surgery. Components: porcine pericardial leaflets/skirt on self-expanding Nitinol frame; delivery catheter system (DCS) with AccuTrak stability layer; compression loading system (CLS). Used in hospital cath lab/OR; operated by interventional cardiologists/cardiac surgeons. Device compressed via CLS, loaded into DCS, and deployed percutaneously. Provides hemodynamic relief for severe aortic stenosis. Output is prosthetic valve function; monitored via echocardiography. Benefits include symptom relief, improved functional status/QoL, and less invasive procedure compared to SAVR.

## Clinical Evidence

Prospective, randomized, unblinded, multi-center trial (IDE G100012) comparing TAVR (n=394) vs. SAVR (n=401) in high-risk patients. Primary endpoint: all-cause mortality at 12 months. TAVR mortality (14.2%) was non-inferior to SAVR (19.1%) (p<0.0001) and met pre-specified superiority criteria (p=0.0377). Secondary endpoints included MACCE, NYHA class, and KCCQ scores. TAVR showed improved hemodynamics (mean gradient, EOA) and functional status. Higher rates of permanent pacemaker implantation and residual aortic regurgitation observed in TAVR arm.

## Technological Characteristics

Valve: porcine pericardium leaflets/skirt, self-expanding Nitinol frame, alpha-amino oleic acid (AOA) antimineralization treatment. Sizes: 23, 26, 29, 31 mm. Delivery: 18Fr catheter with AccuTrak stability layer. Loading: reduction cones/tubing system. Radiopaque markers. Sterilization: not specified. Connectivity: none.

## Regulatory Identification

To replace a patient's aortic heart valve.  They are different from the classified device (heart valves) in that they are placed percutaneously and do not require open chest surgery or a cardiotomy for placement.

## Submission Summary (Full Text)

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# SUMMARY OF SAFETY AND EFFECTIVENESS DATA

## I. GENERAL INFORMATION

|  Device Generic Name: | Aortic valve, prosthesis, percutaneously delivered  |
| --- | --- |
|  Device Trade Name: | Medtronic CoreValve™ system (MCS): transcatheter aortic valve (TAV), models MCS-P4-23-AOA-US (23 mm; CoreValve™ Evolut™), MCS-P3-26-AOA-US (26 mm), MCS-P3-29-AOA-US (29 mm), and MCS-P3-31-AOA-US (31 mm); delivery catheter system (DCS), models DCS-C4-18F-US and DCS-C4-18F-23US; and compression loading system (CLS), model CLS-3000-18F-US  |
|  Device Procode: | NPT  |
|  Applicant Name and Address: | Medtronic CoreValve LLC 3576 Unocal Place Santa Rosa, CA 95403  |
|  Date of Panel Recommendation: | None  |
|  Premarket Approval Application (PMA) Number: | P130021/S002  |
|  Date of FDA Notice of Approval: | June 12, 2014  |
|  Priority Review: | Granted priority review status on March 14, 2014 because the device offers significant advantages over existing approved alternatives.  |

The original PMA P130021 was approved on January 17, 2014 and is indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis (aortic valve area $\leq 0.8$ cm$^2$, a mean aortic valve gradient of $> 40$ mmHg, or a peak aortic-jet velocity of $> 4.0$ m/s) and with native aortic annulus diameters between 18 and 29 mm who are judged by a heart team, including a cardiac surgeon, to be at extreme risk or inoperable for open surgical therapy (predicted risk of operative mortality and/or serious irreversible morbidity $\geq 50\%$ at 30 days). The SSED to support the indication is available on the CDRH website (http://www.accessdata.fda.gov/cdrh_docs/pdf13/P130021b.pdf) and is incorporated by reference here. The current supplement was submitted to expand the indication for the Medtronic CoreValve system.

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## II. INDICATIONS FOR USE

The Medtronic CoreValve™ system is indicated for relief of aortic stenosis in patients with symptomatic heart disease due to severe native calcific aortic stenosis (aortic valve area ≤1.0 cm² or aortic valve area index ≤0.6 cm²/m², a mean aortic valve gradient of ≥40 mm Hg, or a peak aortic-jet velocity of ≥4.0 m/s) and with native anatomy appropriate for the 23, 26, 29, or 31 mm valve system who are judged by a heart team, including a cardiac surgeon, to be at high or greater risk for open surgical therapy (i.e., Society of Thoracic Surgeons operative risk score ≥8% or at a ≥15% risk of mortality at 30 days).

### III. CONTRAINDICATIONS

The Medtronic CoreValve system is contraindicated for patients presenting with any of the following conditions:

- known hypersensitivity or contraindication to aspirin, heparin (HIT/HITTS) and bivalirudin, ticlopidine, clopidogrel, Nitinol (Titanium or Nickel), or sensitivity to contrast media, which cannot be adequately premedicated
- ongoing sepsis, including active endocarditis
- pre-existing mechanical heart valve in aortic position

### IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Medtronic CoreValve system labeling.

### V. DEVICE DESCRIPTION

The Medtronic CoreValve system (MCS) is designed to replace the native aortic heart valve without open heart surgery and without concomitant surgical removal of the failed native valve. It consists of 3 components: the transcatheter aortic valve (TAV), the delivery catheter system (DCS), and the compression loading system (CLS).

#### V.1. Transcatheter Aortic Valve (TAV)

The TAV (Figure 1) is manufactured by suturing three valve leaflets and skirt, made from a single layer of porcine pericardium, onto a self-expanding, multi-level, radiopaque frame made of Nitinol. The bioprosthesis is processed with alpha-amino oleic acid (AOA®), which is an antimineralization treatment derived from oleic acid, a naturally occurring long-chain fatty acid.

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![img-0.jpeg](img-0.jpeg)

Figure 1: CoreValve Transcatheter Aortic Valve

The TAV is available for a range of aortic annulus and ascending aorta diameters as shown in Table 1. Note that the 23 mm TAV has its own device name, called CoreValve™ Evolut™.

Table 1: Patient Anatomical Diameters

|  Bioprosthesis Model | Size | Aortic Annulus Diameter | Ascending Aorta Diameter  |
| --- | --- | --- | --- |
|  **CoreValve™ Evolut™ Bioprosthesis**  |   |   |   |
|  MCS-P4-23-AOA-US | 23 mm | 18 mm–20 mm | ≤34 mm  |
|  **CoreValve™ Bioprosthesis**  |   |   |   |
|  MCS-P3-26-AOA-US | 26 mm | 20 mm–23 mm | ≤40 mm  |
|  MCS-P3-29-AOA-US | 29 mm | 23 mm–26 mm | ≤43 mm  |
|  MCS-P3-31-AOA-US | 31 mm | 26 mm–29 mm | ≤43 mm  |

### V.2. Delivery Catheter System with AccuTrak Stability Layer (AccuTrak DCS)

The DCS (Figure 2) is used to deploy the TAV. The TAV is loaded within the capsule which features an atraumatic, radiopaque tip and protective sheath. The AccuTrak stability layer is fixed at the handle and extends down the outside of the catheter shaft to provide a barrier between the catheter and vessel walls. The handle features macro and micro adjustment control of the retractable capsule sheath. There are two models of the DCS: model DCS-C4-18F-23US for the 23 mm TAV only and model DCS-C4-18F-US for the 26, 29, and 31 mm TAVs.

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![img-1.jpeg](img-1.jpeg)

Figure 2: CoreValve Delivery Catheter System

### V.3. Compression Loading System (CLS)

The CLS (Figure 3) is a system of reduction cones and tubing designed to compress the TAV to an optimal diameter for manual loading into the DCS. Only one model of the CLS is available, i.e., model CLS-3000-18F-US.

![img-2.jpeg](img-2.jpeg)

Figure 3: CoreValve Compression Loading System

The CLS comprises the following elements:

1. Inflow tube (straight tube)
2. Outflow cone
3. Outflow cap
4. Outflow tube (tube with flared ends)
5. Inflow cone

### VI. ALTERNATIVE PRACTICES AND PROCEDURES

Alternatives for patients deemed to be at high risk for surgical aortic valve replacement include: surgical aortic valve replacement (SAVR), treatment with other approved transcatheter aortic valve implantation therapy, temporary relief using a percutaneous technique called balloon aortic valvuloplasty (BAV), or medical therapy (no obstruction-relieving intervention). Each alternative has its own advantages and

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disadvantages. A patient should fully discuss these alternatives with his/her physician to select the treatment option that best meets their needs.

## **VII. MARKETING HISTORY**

The current Medtronic CoreValve system is commercially available in over 70 countries, as listed in Table 2. It has not been withdrawn from marketing for any reason related to its safety or effectiveness.

**Table 2: Countries where Medtronic CoreValve system is commercialized**

|  **Commercially Available**  |   |   |   |
| --- | --- | --- | --- |
|  Afghanistan | Finland | Moldova | Tajikistan  |
|  Albania | France | Netherlands | Thailand  |
|  Argentina | Georgia | New Zealand | Turkmenistan  |
|  Armenia | Germany | Panama | Turkey  |
|  Austria | Greece | Peru | United Kingdom  |
|  Azerbaijan | Guatemala | Philippines | Croatia  |
|  Belgium | Hong Kong | Poland | Israel  |
|  Belarus | Hungary | Portugal | Ukraine  |
|  Bosnia & Herzegovina | Ireland | Romania | Uruguay  |
|  Brazil | Israel | Russia | United States  |
|  Canada | Italy | Saudi Arabia | Uzbekistan  |
|  Chile | Kazakhstan | Serbia | Venezuela  |
|  Colombia | Kyrgyzstan | Slovakia |   |
|  Croatia | Latvia | Slovenia |   |
|  Cyprus | Lithuania | South Africa |   |
|  Czech Republic | Luxembourg | South Korea |   |
|  Denmark | Malaysia | Spain |   |
|  Dominican Republic | Malta | Sweden |   |
|  Ecuador | Mexico | Switzerland |   |
|  Estonia | Montenegro | Taiwan |   |

## **VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH**

Potential risks associated with the implantation of the Medtronic CoreValve system may include, but are not limited to, the following:

- death
- cardiac arrest
- coronary occlusion, obstruction, or vessel spasm (including acute coronary closure)
- emergent surgery (e.g., coronary artery bypass, heart valve replacement, valve explant)
- multi-organ failure
- heart failure

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- myocardial infarction (MI)
- cardiogenic shock
- respiratory insufficiency or respiratory failure
- cardiovascular injury (including rupture, perforation, or dissection of vessels, ventricle, myocardium, or valvular structures that may require intervention)
- ascending aorta trauma
- cardiac tamponade
- cardiac failure or low cardiac output
- prosthetic valve dysfunction including, but not limited to, fracture; bending (out-of-round configuration) of the valve frame; under-expansion of the valve frame; calcification; pannus; leaflet wear, tear, prolapse, or retraction; poor valve coaptation; suture breaks or disruption; leaks; mal-sizing (prosthesis-patient mismatch); malposition (either too high or too low)/malplacement; regurgitation; stenosis
- thrombosis/embolus (including valve thrombosis)
- valve migration/valve embolization
- ancillary device embolization
- emergent percutaneous coronary intervention (PCI)
- emergent balloon valvuloplasty
- major or minor bleeding that may or may not require transfusion or intervention (including life-threatening or disabling bleeding)
- allergic reaction to antiplatelet agents, contrast medium, or anesthesia
- infection (including septicemia and endocarditis)
- stroke, transient ischemic attack (TIA), or other neurological deficits
- permanent disability
- renal insufficiency or renal failure (including acute kidney injury)
- mitral valve regurgitation or injury
- tissue erosion
- vascular access related complications (e.g., dissection, perforation, pain, bleeding, hematoma, pseudoaneurysm, irreversible nerve injury, compartment syndrome, arteriovenous fistula, stenosis)
- conduction system disturbances (e.g., atrioventricular node block, left-bundle branch block, asystole), which may require a permanent pacemaker
- cardiac arrhythmias
- encephalopathy
- pulmonary edema
- pericardial effusion
- pleural effusion
- myocardial ischemia
- peripheral ischemia
- bowel ischemia
- heart murmur
- hemolysis
- cerebral infarction-asymptomatic

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- non-emergent reoperation
- inflammation
- fever
- hypotension or hypertension
- syncope
- dyspnea
- anemia
- angina
- abnormal lab values (including electrolyte imbalance)

For the specific adverse events that occurred in the clinical study, please see Section X.

### IX. SUMMARY OF PRECLINICAL STUDIES

No additional preclinical testing was necessary for the current supplement. A summary of previously reported preclinical studies can be found in the SSED for the original PMA (http://www.accessdata.fda.gov/cdrh_docs/pdf13/P130021b.pdf).

### X. SUMMARY OF PRIMARY CLINICAL STUDY

A clinical study was conducted to establish a reasonable assurance of safety and effectiveness of transcatheter aortic valve replacement (TAVR) therapy with the Medtronic CoreValve system as compared with surgical aortic valve replacement (SAVR) in patients with severe symptomatic native aortic valve stenosis who were deemed to be at high risk for open surgical therapy. The study was conducted in the U.S. under IDE G100012. A summary of the clinical study is presented below.

### A. Study Design

The CoreValve U.S. pivotal trial consisted of two patient cohorts, i.e., the Extreme Risk Cohort, which was presented in the original PMA (P130021), and the High Risk Cohort. The High Risk Cohort presented herein was a prospective, randomized, unblinded, multi-center investigational study. Patients who were determined to be at high risk for SAVR were randomized to treatment with either TAVR or SAVR. Randomization was stratified by suitability for potential iliofemoral delivery (as assessed prior to randomization) of the CoreValve system. Of the 795 patients enrolled into the trial, 394 were randomized to TAVR (330 for iliofemoral and 64 for non-iliofemoral) and 401 to SAVR (333 iliofemoral eligible patients and 68 non-iliofemoral eligible patients). Non-iliofemoral access included subclavian and direct aortic routes. The trial patient flowchart is shown in Figure 4.

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![img-3.jpeg](img-3.jpeg)

**Figure 4: CoreValve High Risk Cohort Patient Flow-chart – ITT Population**

The trial was conducted at 45 investigational sites. A total of 795 patients were enrolled between February 02, 2011 and July 23, 2013. The database for this PMA supplement reflected data from events through November 8, 2013. Contractors were utilized for interpretation and analysis of data for several aspects of the study, including an independent Data Safety Monitoring Board (DSMB) that could contract an independent statistician, a Clinical Events Committee (CEC) that was responsible for adjudicating adverse events, an echocardiography core laboratory, and a quality of life (QoL) core laboratory.

1. Clinical Inclusion and Exclusion Criteria

Because tools such as the Society of Thoracic Surgeons (STS) risk calculator can only accommodate a limited number of risk factors and do not account for frailty, disabilities and anatomical characteristics that confer a prohibitive risk for SAVR (e.g., porcelain aorta), these tools were not used as stand-alone mechanisms for identifying patients at high risk for cardiac surgery. Therefore, a team of two cardiac surgeons and one interventional cardiologist at each investigational site were required to assess patient suitability for inclusion in the study, taking into account risk factors

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not covered by the STS risk calculator. A central screening committee made a subsequent assessment of patient risk and agreed on patient eligibility or ineligibility.

The inclusion and exclusion criteria for the study are summarized below:

# Inclusion Criteria

- Subject must have co-morbidities such that one cardiologist and two cardiac surgeons agree predicted risk of operative mortality is ≥15% (and predicted operative mortality or serious, irreversible morbidity risk of < 50%) at 30 days
- Subject has senile degenerative aortic valve stenosis with:
  o mean gradient > 40 mmHg or jet velocity greater than 4.0 m/sec by either resting or dobutamine stress echocardiogram, or simultaneous pressure recordings at cardiac catheterization (either resting or dobutamine stress), AND
  o an initial aortic valve area of ≤ 0.8 cm² (or aortic valve area index ≤ 0.5 cm²/m²) by resting echocardiogram or simultaneous pressure recordings at cardiac catheterization
- Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New York Heart Association (NYHA) Functional Class II or greater
- The subject or the subject's legal representative has been informed of the nature of the trial, agrees to its provisions and has provided written informed consent as approved by the IRB of the respective clinical site
- The subject and the treating physician agree that the subject will return for all required post-procedure follow-up visits

# Exclusion Criteria

# Clinical

- Evidence of an acute myocardial infarction ≤ 30 days before the intended treatment
- Any percutaneous coronary or peripheral interventional procedure performed within 30 days prior to the index procedure including bare metal stents. Additionally, any drug eluting stents placed within 6 months prior to the index procedure
- Blood dyscrasias as defined: leukopenia (WBC < 1000mm³), thrombocytopenia (platelet count <50,000 cells/mm³), history of bleeding diathesis or coagulopathy
- Untreated clinically significant coronary artery disease requiring revascularization
- Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support
- Need for emergency surgery for any reason
- Severe ventricular dysfunction with left ventricular ejection fraction (LVEF) < 20% as measured by resting echocardiogram
- Recent (within 6 months) cerebrovascular accident (CVA) or transient ischemic attack (TIA)

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- End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min
- Active Gastrointestinal (GI) bleeding within the past 3 months
- A known hypersensitivity or contraindication to any of the following which cannot be adequately pre-medicated:
  - aspirin
  - heparin (HIT/HITTS)
  - nitinol (titanium or nickel)
  - ticlopidine and clopidogrel
  - contrast media
- Ongoing sepsis, including active endocarditis
- Subject refuses a blood transfusion
- Life expectancy < 12 months due to associated non-cardiac co-morbid conditions.
- Other medical, social, or psychological conditions that in the opinion of an Investigator precludes the subject from appropriate consent
- Severe dementia (resulting in either inability to provide informed consent for the trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate rehabilitation from the procedure or compliance with follow-up visits)
- Currently participating in an investigational drug or another device trial
- Symptomatic carotid or vertebral artery disease
- Subject has been offered surgical aortic valve replacement but declined

# Anatomical

- Native aortic annulus size < 18 mm or > 29 mm per the baseline diagnostic imaging
- Pre-existing prosthetic heart valve in any position
- Mixed aortic valve disease (aortic stenosis and aortic regurgitation with predominant aortic regurgitation (3-4+))
- Moderate to severe (3-4+) or severe (4+) mitral or severe (4+) tricuspid regurgitation
- Moderate to severe mitral stenosis
- Hypertrophic obstructive cardiomyopathy
- New or untreated echocardiographic evidence of intracardiac mass, thrombus or vegetation
- Severe basal septal hypertrophy with an outflow gradient
- Aortic root angulation (angle between plane of aortic valve annulus and horizontal plane/vertebrae) > 70° (for femoral and left subclavian/axillary access) and > 30° (for right subclavian/axillary access)
- Ascending aorta that exceeded the maximum diameter for any given native aortic annulus size
- Congenital bicuspid or unicuspid valve verified by echocardiography
- Sinus of valsalva anatomy that would prevent adequate coronary perfusion
- Vascular Transarterial access not able to accommodate an 18Fr sheath

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## 2. Follow-Up Schedule

Follow-up periods were discharge or 7 days, whichever comes first, 30 days, 6 months, 12 months, and annually thereafter to a minimum of 5 years post procedure. Patients were followed for a minimum of 12 months prior to submission of this PMA application.

## 3. Clinical Endpoints

### Primary Safety and Effectiveness Endpoints

The primary endpoint was all-cause mortality rate at 12 months. The primary hypothesis was that TAVR with the Medtronic CoreValve system was non-inferior to SAVR for the primary endpoint, as expressed as follows:

$$H_0: \pi_{\text{MCS TAVR}} \geq \pi_{\text{SAVR}} + 7.5\%$$

$$H_A: \pi_{\text{MCS TAVR}} < \pi_{\text{SAVR}} + 7.5\%$$

where $\pi_{\text{MCS TAVR}}$ and $\pi_{\text{SAVR}}$ represent the event rate for the primary endpoint for the CoreValve arm and the SAVR arm, respectively. Assuming that non-inferiority was proven at the one-sided 0.05 level, a subsequent pre-specified test for superiority would be performed at the one-sided 0.05 level. Because this was a closed test procedure, no adjustment for multiplicity was needed.

### Secondary Safety and Effectiveness Endpoints

The study included the following secondary endpoints:

1. 1. Major adverse cardiovascular or cerebrovascular event (MACCE; defined as a composite of all-cause mortality, MI, all stroke, and aortic valve reintervention) at 30 days, 6 months, 12 months and annually thereafter up to 5 years
2. 2. The occurrence of individual MACCE components at 30 days, 6 months, 12 months and annually thereafter up to 5 years
3. 3. Major adverse events (MAE) at 30 days, 6 months, 12 months and annually thereafter up to 5 years
4. 4. Conduction disturbance requiring permanent pacemaker implantation (PPI) at 30 days, 6 months, 12 months and annually thereafter up to 5 years
5. 5. Change in NYHA class from baseline at 30 days, 6 months, 12 months and annually thereafter up to 5 years
6. 6. Change in distance walked during 6-minute walk test (6MWT) from baseline to 30 days and baseline to 12 months
7. 7. Ratio of days alive out of hospital versus total days alive assessed at 12 months follow-up
8. 8. QoL change from baseline at 30 days, 6 months, 12 months and annually thereafter up to 5 years
9. 9. Echocardiographic assessment of valve performance at discharge, 30 days, 6 months, 12 months and annually thereafter up to 5 years using the following measures:

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- Transvalvular mean gradient
- Effective orifice area (EOA)
- Degree of aortic regurgitation (transvalvular and paravalvular)
10. Aortic valve disease hospitalization at 30 days, 6 months, 12 months and annually thereafter up to 5 years
11. Cardiovascular deaths and valve-related deaths at 30 days, 6 months, 12 months and annually thereafter up to 5 years
12. Strokes and transient ischemic attacks (TIAs) at 30 days, 6 months, 12 months and annually thereafter up to 5 years
13. Index procedure related MAEs
14. Length of index procedure hospital stay
15. Device success defined as follows:
- Successful vascular access, delivery and deployment of the device, and successful retrieval of the delivery system
- Correct position of the device in the proper anatomical location (placement in the annulus with no impedance on device function)
- Intended performance of the prosthetic valve (aortic valve area > 1.2 cm² for 26, 29, and 31 mm valves, ≥ 0.9 cm² for 23 mm valve (by echocardiography using the continuity equation) and mean aortic valve gradient < 20 mmHg or peak velocity < 3 m/sec, without moderate or severe prosthetic valve AR). Performance is assessed acutely in a resting state, either within 24-48 hours after the index procedure or before hospital discharge
- Only one valve implanted in the proper anatomical location
16. Procedural success, defined as device success and absence of in-hospital MACCE
17. Evidence of prosthetic valve dysfunction at 30 days, 6 months, 12 months and annually thereafter up to 5 years

Note: Secondary endpoints #15-17 were only for the TAVR cohort.

Six (6) of the above secondary endpoints were included in a hierarchical testing protocol, namely, changes from baseline to 12 months in transvalvular mean gradient, effective orifice area, NYHA classification, and KCCQ score, MACCE rate at 30 days or hospital discharge, whichever was later, and change from baseline to 1 month in SF-12.

The MACCE rate was also a powered secondary endpoint, with the following superiority hypothesis that TAVR with CoreValve was superior to SAVR in the binary rate of MACCE at 30 days or hospital discharge, whichever was longer:

$$\mathrm{H}_{0}: \pi_{\mathrm{MCS\ TAVR}} = \pi_{\mathrm{SAVR}}$$

$$\mathrm{H}_{\mathrm{A}}: \pi_{\mathrm{MCS\ TAVR}} < \pi_{\mathrm{SAVR}}$$

where $\pi_{\mathrm{MCS\ TAVR}}$ and $\pi_{\mathrm{SAVR}}$ represent the MACCE rate for the CoreValve arm and the SAVR arm, respectively.

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### **B. Accountability of PMA Cohort**

At the time of database lock, 734 of the 795 patients enrolled were available for assessment of the primary endpoint. Table 3 depicts the disposition of patients at each follow-up period for the Intent-to-Treat population (see Analysis Population section for definition).

**Table 3: Overall Study Compliance**

|  Follow up Period | Variable | TAVR N=394 | SAVR N=401  |
| --- | --- | --- | --- |
|  1 month | Expected | 375 | 344  |
|   |  Number withdrew | 2 | 37  |
|   |  Number died before visit | 17 | 18  |
|   |  Lost to follow up | 0 | 0  |
|   |  Other | 0 | 1  |
|   |  Visit Pending | 0 | 1  |
|   |  Visit compliance | 98.1% (368) | 95.6% (329)  |
|  6 months | Expected | 353 | 304  |
|   |  Number withdrew | 0 | 3  |
|   |  Number died before visit | 21 | 37  |
|   |  Lost to follow up | 0 | 0  |
|   |  Other | 0 | 0  |
|   |  Visit Pending | 1 | 0  |
|   |  Visit compliance | 95.2% (336) | 91.8% (279)  |
|  12 months | Expected | 325 | 282  |
|   |  Number withdrew | 2 | 3  |
|   |  Number died before visit | 24 | 18  |
|   |  Lost to follow up | 0 | 0  |
|   |  Other | 0 | 1  |
|   |  Visit Pending | 2 | 0  |
|   |  Visit compliance | 98.5% (320) | 93.6% (264)  |
|  * Visit Pending: Since 23mm candidates continued to be enrolled through July 2013, these subjects have 1 month, 6 month, or 12 month visits pending.  |   |   |   |

### **C. Study Population Demographics and Baseline Parameters**

The demographics of the study population were typical for an aortic stenosis valve replacement study performed in the U.S., as shown in Table 4. A high proportion of the patients had significant co-morbidities, frailties, or disabilities, and these risk factors were generally well balanced between the study arms. The mean age for patients participating in the trial was approximately 83 years old, and slightly greater than 50% of patients were male. The mean STS score was approximately 7. In addition, approximately 85% of all patients were in NYHA classes III or IV.

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**Table 4: Demographics of the Study Population (ITT)**

|  Demographic | Iliofemoral |   | Non-Iliofemoral |   | Pooled  |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |  TAVR N=330 | SAVR N=333 | TAVR N=64 | SAVR N=68 | TAVR N=394 | SAVR N=401 | P- Values  |
|  Age (yrs) | 83.4 ± 6.8 | 83.6 ± 6.3 | 81.8 ± 8.0 | 82.9 ± 6.5 | 83.2 ± 7.1 | 83.5 ± 6.3 | 0.5102  |
|  Gender (Male) | 53.9% (178/330) | 53.8% (179/333) | 51.6% (33/64) | 48.5% (33/68) | 53.6% (211/394) | 52.9% (212/401) | 0.8464  |
|  NYHA Classification |  |  |  |  |  |  |   |
|  II | 13.0% (43/330) | 12.0% (40/333) | 20.3% (13/64) | 19.1% (13/68) | 14.2% (56/394) | 13.2% (53/401) | 0.6723  |
|  III | 65.2% (215/330) | 69.7% (232/333) | 67.2% (43/64) | 66.2% (45/68) | 65.5% (258/394) | 69.1% (277/401) |   |
|  IV | 21.8% (72/330) | 18.3% (61/333) | 12.5% (8/64) | 14.7% (10/68) | 20.3% (80/394) | 17.7% (71/401) |   |
|  STS Score (Risk of Mortality, %) | 7.3 ± 3.1 | 7.5 ± 3.1 | 7.2 ± 2.6 | 7.6 ± 3.9 | 7.3 ± 3.0 | 7.5 ± 3.2 | 0.2680  |
|  Coronary Artery Disease | 75.5% (249/330) | 74.2% (247/333) | 75.0% (48/64) | 86.8% (59/68) | 75.4% (297/394) | 76.3% (306/401) | 0.7597  |
|  Previous MI | 23.3% (77/330) | 23.4% (78/333) | 37.5% (24/64) | 29.4% (20/68) | 25.6% (101/394) | 24.4% (98/401) | 0.6972  |
|  Previous Interventions |  |  |  |  |  |  |   |
|  Coronary Artery Bypass Surgery | 31.2% (103/330) | 29.1% (97/333) | 21.9% (14/64) | 35.3% (24/68) | 29.7% (117/394) | 30.2% (121/401) | 0.8828  |
|  Percutaneous Coronary Intervention | 32.1% (106/330) | 37.8% (126/333) | 42.2% (27/64) | 38.2% (26/68) | 33.8% (133/394) | 37.9% (152/401) | 0.2226  |
|  Balloon Valvuloplasty | 4.5% (15/330) | 6.3% (21/333) | 12.5% (8/64) | 7.4% (5/68) | 5.8% (23/394) | 6.5% (26/401) | 0.7048  |
|  Cerebral Vascular Disease | 24.7% (81/328) | 23.2% (77/332) | 29.0% (18/62) | 35.9% (23/64) | 25.4% (99/390) | 25.3% (100/396) | 0.9660  |
|  Prior Stroke | 13.6% (45/330) | 12.6% (42/333) | 9.4% (6/64) | 16.4% (11/67) | 12.9% (51/394) | 13.3% (53/400) | 0.8984  |
|  Peripheral Vascular Disease | 37.6% (123/327) | 37.2% (123/331) | 62.5% (40/64) | 68.7% (46/67) | 41.7% (163/391) | 42.5% (169/398) | 0.8257  |
|  Chronic Lung Disease/COPD | 44.5% (147/330) | 46.2% (154/333) | 45.3% (29/64) | 38.2% (26/68) | 44.7% (176/394) | 44.9% (180/401) | 0.9508  |
|  Home Oxygen | 13.4% (44/329) | 12.3% (41/333) | 9.4% (6/64) | 10.3% (7/68) | 12.7% (50/393) | 12.0% (48/401) | 0.7472  |
|  Creatinine Level >2 mg/dl | 3.3% (11/330) | 4.5% (15/333) | 3.1% (2/64) | 5.9% (4/68) | 3.3% (13/394) | 4.7% (19/401) | 0.3021  |
|  Atrial Fibrillation / Atrial Flutter | 40.6% (134/330) | 48.8% (162/332) | 42.9% (27/63) | 41.2% (28/68) | 41.0% (161/393) | 47.5% (190/400) | 0.0640  |
|  Pre-Existing Permanent Pacemaker Placement / ICD | 24.8% (82/330) | 21.6% (72/333) | 15.6% (10/64) | 16.2% (11/68) | 23.4% (92/394) | 20.7% (83/401) | 0.3669  |
|  Aorta Calcification^{1} |  |  |  |  |  |  |   |
|  Severe | 10.6% (35/330) | 10.5% (35/333) | 19.0% (12/63) | 16.2% (11/68) | 12.0% (47/393) | 11.5% (46/401) | 0.8307  |
|  Porcelain | 0.0% (0/330) | 0.0% (0/333) | 1.6% (1/63) | 0.0% (0/68) | 0.3% (1/393) | 0.0% (0/401) | 0.4950  |
|  Chest Wall Deformity | 1.8% (6/330) | 0.3% (1/333) | 4.7% (3/64) | 0.0% (0/68) | 2.3% (9/394) | 0.2% (1/401) | 0.0106  |

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|  Demographic | Iliofemoral |   | Non-Iliofemoral |   | Pooled  |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |  TAVR N=330 | SAVR N=333 | TAVR N=64 | SAVR N=68 | TAVR N=394 | SAVR N=401 | P- Values  |
|  Hostile Mediastinum | 3.9% (13/330) | 0.9% (3/331) | 3.1% (2/64) | 2.9% (2/68) | 3.8% (15/394) | 1.3% (5/399) | 0.0218  |
|  Cirrhosis of the Liver | 2.4% (8/330) | 1.8% (6/333) | 3.1% (2/64) | 1.5% (1/68) | 2.5% (10/394) | 1.7% (7/401) | 0.4400  |
|  Wheelchair Bound | 4.8% (16/330) | 7.5% (25/333) | 0.0% (0/64) | 7.4% (5/68) | 4.1% (16/394) | 7.5% (30/401) | 0.0389  |
|  Echocardiographic Findings |  |  |  |  |  |  |   |
|  Ejection Fraction (visual estimate, %) | 58.1 ± 10.9 | 57.5 ± 11.8 | 57.4 ± 13.4 | 58.3 ± 12.4 | 58.0 ± 11.3 | 57.7 ± 11.9 | 0.7110  |
|  Aortic Valve Area (cm^{2}) | 0.72 ± 0.23 | 0.73 ± 0.24 | 0.70 ± 0.18 | 0.71 ± 0.22 | 0.72 ± 0.23 | 0.73 ± 0.23 | 0.5801  |
|  Mean Gradient across Aortic Valve (MGV_{2}, mmHg) | 48.36 ± 15.09 | 47.69 ± 14.39 | 47.38 ± 16.74 | 48.08 ± 12.51 | 48.20 ± 15.35 | 47.75 ± 14.07 | 0.6725  |
|  Mitral Regurgitation: Moderate/Severe | 10.2% (33/325) | 10.5% (34/324) | 8.1% (5/62) | 9.0% (6/67) | 9.8% (38/387) | 10.2% (40/391) | 0.8486  |
|  ^{1} Aorta Calcification is measured on screening CT Angiogram Plus-minus values present the mean ± standard deviation.  |   |   |   |   |   |   |   |

The STS score predicted a 30-day mortality of 7.5% for the average surgeon at the average hospital. The Kaplan-Meier (K-M) 30-day mortality for the As Treated SAVR arm was 4.5%. Therefore, the observed/expected ratio was 0.60 in this trial, indicating better than average care in the SAVR arm.

## **D. Safety and Effectiveness Results**

### **1. Analysis Populations**

The “Intent-to-Treat” (ITT) population consisted of all randomized patients. Patients were analyzed according to the randomization assignment and the access site eligibility stratification (iliofemoral or non-iliofemoral), regardless of whether a procedure was actually attempted, which device the patient actually received, and which access site was actually used.

The “As Treated” (AT) population consisted of all ITT patients with an attempted implant procedure, defined as when the patient was brought into the procedure room and any of the following had occurred: anesthesia administered, vascular line placed, TEE placed or any monitoring line placed. The AT population was the primary analysis population.

The “Implanted” population consisted of all AT patients who were actually implanted with either CoreValve or a surgical valve. To be considered implanted, a TAVR patient’s device disposition form must show at least one CoreValve device with a

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final disposition of “Implanted,” while an SAVR patient’s procedure form must indicate the valve manufacturer and model as well as the suture method.

The “Per Protocol” population consisted of all implanted subjects who: (1) were implanted according to their randomization and access site stratification; (2) had at least 12 months (365 days) of follow-up or had experienced the primary endpoint (death) prior to 12 months; (3) did not cross to a different type of procedure from their first attempted procedure types (TAVR or SAVR) before their 12 month visit; and (4) had satisfied all inclusion/exclusion criteria.

The “Modified Per Protocol” population consisted of all implanted subjects who: (1) were implanted according to their randomization and access site stratification; (2) did not cross to a different type of procedure from their first attempted procedure types (TAVR or SAVR) before their 12 month visit; and (3) had satisfied all inclusion/exclusion criteria.

For subgroup analyses on the AT and Implanted populations, TAVR patients were analyzed according to the access site (iliofemoral or non-iliofemoral) on the first attempted procedure form, while SAVR patients were analyzed according to the stratified access designation (iliofemoral or non-iliofemoral).

## 2. Primary Safety and Effectiveness Endpoint

The K-M rate of all-cause mortality at 12 months was 14.22% for TAVR and 19.12% for SAVR (Table 5). The difference between the two rates was -4.89% with an upper 1-sided 95% CI of -0.37%, which was statistically less than the pre-specified non-inferiority margin of 7.5% (p<0.0001). Therefore, the null hypothesis that TAVR was inferior to SAVR for the primary endpoint of all-cause mortality at 12 months was rejected and the alternative hypothesis that TAVR was non-inferior to SAVR within a non-inferiority margin of 7.5% was accepted. Subsequently, a pre-specified test for superiority of TAVR over SAVR was also conducted, which demonstrated that the rate of all-cause mortality at 12 months for TAVR was significantly less than that for SAVR at the one-sided 0.05 level (p=0.0377).

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**Table 5: Primary Endpoint: All-Cause Mortality at 12 Months – As Treated Population**

|   | TAVR N=390 | SAVR N=357  |
| --- | --- | --- |
|  **Total # of Patients** | **390** | **357**  |
|  # of Patients Died within 1 Year | 55 | 67  |
|  # of Patients Censored prior to 1 Year | 7 | 16  |
|  # of Patients Alive at 1 Year | 328 | 274  |
|  **Mortality Rate at 1 Year (K-M)** | **14.22%** | **19.12%**  |
|  Standard Error at 1 Year | 1.78% | 2.10%  |
|  Mortality Difference (TAVR-SAVR) | -4.89%  |   |
|  Standard Error of Difference | 2.75%  |   |
|  95% 1-sided UCB for Difference | -0.37%  |   |
|  **Primary Objective – Non-Inferiority** |  |   |
|  Non-inferiority Margin | 7.50%  |   |
|  Z-Score | -4.5019  |   |
|  P-Value | <0.0001  |   |
|  Non-Inferiority Test | Passed  |   |
|  **Primary Objective – Superiority** |  |   |
|  Z-Score | -1.7776  |   |
|  P-Value | 0.0377  |   |
|  Superiority Test | Passed  |   |

The primary endpoint of all-cause mortality at 12 months included all deaths (cardiovascular and non-cardiovascular) from any cause after a valve intervention. Figure 5 and Table 6 show the K-M rates of all-cause mortality in the AT population for both study arms up to 12-month follow-up.

![img-4.jpeg](img-4.jpeg)

**Figure 5: All-Cause Mortality Kaplan-Meier Event Rate – As Treated Population**

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**Table 6: Primary Endpoint: All-Cause Mortality – As Treated Population**

|  Interval Post Procedure (months)* | TAVR N=390 |   |   |   | SAVR N=357  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  0 | 1 | 6 | 12 | 0 | 1 | 6 | 12  |
|  # at start of interval | 390 | 377 | 353 | 329 | 357 | 341 | 297 | 274  |
|  # events in interval | 13 | 22 | 19 | 20 | 15 | 35 | 17 | 17  |
|  # event cumulative | 13 | 35 | 54 | 74 | 15 | 50 | 67 | 84  |
|  K-M Event Rate | 1.3 | 3.3 | 9.0 | 14.2 | 0.0 | 4.5 | 14.1 | 19.1  |
|  Lower 95% CI | 0.2 | 1.6 | 6.2 | 10.7 | NA | 2.3 | 10.5 | 15.0  |
|  Upper 95% CI | 2.4 | 5.1 | 11.8 | 17.7 | NA | 6.6 | 17.7 | 23.2  |
|  *0 = 0-29 days, 1 = 30-182 days, 6 = 183-364 days, 12 ≥ 365 days.  |   |   |   |   |   |   |   |   |
|  Cumulative probability of event estimate is based on the Kaplan-Meier method  |   |   |   |   |   |   |   |   |

The primary endpoint hypothesis testing was also pre-specified for the ITT, Implanted, and Per Protocol populations, as presented in Tables 7 - 10 and Figures 6 - 8. Non-inferiority of TAVR compared to SAVR was concluded for all analysis populations (p<0.0001 for all). Subsequent superiority null hypothesis was rejected at one-sided 0.05 level for the ITT (p=0.0365) and Implanted (p=0.042) populations, but not for the Per Protocol population (p=0.07).

**Table 7: Primary Endpoint: All-Cause Mortality at 12 Months – Pre-specified Additional Populations**

|   | Intent-to-Treat |   | Implanted |   | Per Protocol  |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  TAVR N=394 | SAVR N=401 | TAVR N=389 | SAVR N=353 | TAVR N=365 | SAVR N=326  |
|  **Total # of Patients** | 394 | 401 | 389 | 353 | 365 | 326  |
|  # of Patients Died within 1 Year | 54 | 68 | 55 | 66 | 53 | 61  |
|  # of Patients Censored prior to 1 Year | 9 | 54 | 7 | 15 | 0 | 0  |
|  # of Patients Alive at 1 Year | 331 | 279 | 327 | 272 | 312 | 265  |
|  **Mortality Rate at 1 Year (K-M)** | **13.87%** | **18.70%** | **14.26%** | **19.03%** | **14.52%** | **18.71%**  |
|  Standard Error at 1 Year | 1.75% | 2.05% | 1.78% | 2.11% | 1.84% | 2.16%  |
|  Mortality Difference (TAVR-SAVR) | -4.83% |   | -4.77% |   | -4.19%  |   |
|  Standard Error of Difference | 2.70% |   | 2.76% |   | 2.84%  |   |
|  95% 1-sided UCB for Difference | -0.40% |   | -0.23% |   | 0.48%  |   |
|  **Primary Objective – Non-Inferiority** |   |   |   |   |   |   |
|  Non-inferiority Margin | 7.50% |   | 7.50% |   | 7.50%  |   |
|  Z-Score | -4.5734 |   | -4.4443 |   | -4.1164  |   |
|  P-Value | <0.0001 |   | <0.0001 |   | <0.0001  |   |
|  Non-Inferiority Test | Passed |   | Passed |   | Passed  |   |
|  **Primary Objective – Superiority** |   |   |   |   |   |   |
|  Z-Score | -1.7926 |   | -1.7283 |   | -1.4757  |   |
|  P-Value | 0.0365 |   | 0.0420 |   | 0.0700  |   |
|  Superiority Test | Passed |   | Passed |   | Failed  |   |

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![img-5.jpeg](img-5.jpeg)

**Figure 6: All-Cause Mortality Kaplan-Meier Event Rate – Intent-to-Treat Population**

**Table 8: Primary Endpoint: All-Cause Mortality – Intent-to-Treat Population**

|  Interval Post Procedure (months)* | TAVR N=394 |   |   |   | SAVR N=401  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  0 | 1 | 6 | 12 | 0 | 1 | 6 | 12  |
|  # at start of interval | 394 | 384 | 356 | 331 | 401 | 368 | 303 | 279  |
|  # events in interval | 10 | 24 | 20 | 22 | 10 | 43 | 15 | 21  |
|  # event cumulative | 10 | 34 | 54 | 76 | 10 | 53 | 68 | 89  |
|  K-M Event Rate | 0.0 | 2.5 | 8.7 | 13.9 | 0.0 | 2.6 | 14.7 | 18.7  |
|  Lower 95% CI | NA | 1.0 | 5.9 | 10.4 | NA | 1.0 | 11.0 | 14.7  |
|  Upper 95% CI | NA | 4.1 | 11.5 | 17.3 | NA | 4.2 | 18.3 | 22.7  |
|  *0 = 0-29 days, 1 = 30-182 days, 6 = 183-364 days, 12 ≥ 365 days. Cumulative probability of event estimate is based on the Kaplan-Meier method  |   |   |   |   |   |   |   |   |

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![img-6.jpeg](img-6.jpeg)

**Figure 7: All-Cause Mortality Kaplan-Meier Event Rate – Implanted Population**

**Table 9: Primary Endpoint: All-Cause Mortality – Implanted Population**

|  Interval Post Procedure (months)* | TAVR N=389 |   |   |   | SAVR N=353  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  0 | 1 | 6 | 12 | 0 | 1 | 6 | 12  |
|  # at start of interval | 389 | 376 | 352 | 328 | 353 | 337 | 294 | 272  |
|  # events in interval | 13 | 22 | 19 | 20 | 15 | 34 | 17 | 16  |
|  # event cumulative | 13 | 35 | 54 | 74 | 15 | 49 | 66 | 82  |
|  K-M Event Rate | 1.3 | 3.3 | 9.0 | 14.3 | 0.0 | 4.5 | 14.0 | 19.0  |
|  Lower 95% CI | 0.2 | 1.6 | 6.2 | 10.8 | NA | 2.4 | 10.4 | 14.9  |
|  Upper 95% CI | 2.4 | 5.1 | 11.9 | 17.7 | NA | 6.7 | 17.6 | 23.2  |
|  *0 = 0-29 days, 1 = 30-182 days, 6 = 183-364 days, 12 ≥ 365 days. Cumulative probability of event estimate is based on the Kaplan-Meier method  |   |   |   |   |   |   |   |   |

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![img-7.jpeg](img-7.jpeg)

**Figure 8: All-Cause Mortality Kaplan-Meier Event Rate – Per Protocol Population**

**Table 10: Primary Endpoint: All-Cause Mortality – Per Protocol Population**

|  Interval Post Procedure (months)* | TAVR N=365 |   |   |   | SAVR N=326  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  0 | 1 | 6 | 12 | 0 | 1 | 6 | 12  |
|  # at start of interval | 365 | 354 | 332 | 313 | 326 | 313 | 280 | 265  |
|  # events in interval | 11 | 22 | 19 | 20 | 13 | 33 | 15 | 15  |
|  # event cumulative | 11 | 33 | 52 | 72 | 13 | 46 | 61 | 76  |
|  K-M Event Rate | 1.1 | 3.0 | 9.0 | 14.5 | 0.0 | 4.3 | 14.1 | 18.7  |
|  Lower 95% CI | 0.0 | 1.3 | 6.1 | 10.9 | NA | 2.1 | 10.3 | 14.5  |
|  Upper 95% CI | 2.2 | 4.8 | 12.0 | 18.1 | NA | 6.5 | 17.9 | 22.9  |
|  *0 = 0-29 days, 1 = 30-182 days, 6 = 183-364 days, 12 ≥ 365 days.  |   |   |   |   |   |   |   |   |
|  Cumulative probability of event estimate is based on the Kaplan-Meier method  |   |   |   |   |   |   |   |   |

A *post hoc* analysis was also performed on the primary endpoint hypothesis testing for the Modified Per Protocol population. The Modified Per Protocol population included 22 additional subjects (7 TAVR, 15 SAVR) who were censored prior to 1 year as compared with the Per Protocol population. In addition, a *post hoc* analysis was conducted on the worst-case Modified Per Protocol population, which assumed all 7 censored TAVR subjects had died at the censoring time and all 15 censored SAVR subjects were alive at 1 year). In both analyses, non-inferiority was demonstrated. The results are presented in Tables 11 - 13 and Figures 9 and 10.

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Table 11: Primary Endpoint: All-Cause Mortality at 12 Months – post hoc Additional Populations

|   | Modified Per Protocol |   | Modified Per Protocol Worst Case Scenario  |   |
| --- | --- | --- | --- | --- |
|   |  TAVR N=372 | SAVR N=341 | TAVR N=372 | SAVR N=341  |
|  Total # of Patients | 372 | 341 | 372 | 341  |
|  # of Patients Died within 1 Year | 53 | 61 | 60 | 61  |
|  # of Patients Censored prior to 1 Year | 7 | 15 | 0 | 0  |
|  # of Patients Alive at 1 Year | 312 | 265 | 312 | 280  |
|  Mortality Rate at 1 Year (K-M) | 14.38% | 18.21% | 16.13% | 17.89%  |
|  Standard Error at 1 Year | 1.83% | 2.11% | 1.91% | 2.08%  |
|  Mortality Difference (TAVR-SAVR) | -3.83% |   | -1.76%  |   |
|  Standard Error of Difference | 2.79% |   | 2.82%  |   |
|  95% 1-sided UCB for Difference | 0.76% |   | 2.88%  |   |
|  Primary Objective – Non-Inferiority |  |   |   |   |
|  Non-inferiority Margin | 7.50% |   | 7.50%  |   |
|  Z-Score | -4.0572 |   | -3.2853  |   |
|  P-Value | < 0.0001 |   | 0.0005  |   |
|  Non-Inferiority Test | Passed |   | Passed  |   |
|  Subjects (7 TAVR, 15 SAVR) censored before 1 year were included in the modified per protocol. For worst case scenario the following assumptions were made for the censored subjects: the 7 TAVR subjects were assumed to have died on date of censoring and the 15 SAVR subjects were assumed to be alive at 1 year.  |   |   |   |   |

![img-8.jpeg](img-8.jpeg)

Figure 9: All-Cause Mortality Kaplan-Meier Event Rate – Modified Per Protocol Population

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**Table 12: Primary Endpoint: All-Cause Mortality – Modified Per Protocol Population**

|  Interval Post Procedure (months)* | TAVR N=372 |   |   |   | SAVR N=341  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  0 | 1 | 6 | 12 | 0 | 1 | 6 | 12  |
|  # at start of interval | 372 | 361 | 337 | 313 | 341 | 327 | 285 | 265  |
|  # events in interval | 11 | 22 | 19 | 20 | 13 | 33 | 15 | 15  |
|  # event cumulative | 11 | 33 | 52 | 72 | 13 | 46 | 61 | 76  |
|  K-M Event Rate | 1.1 | 3.0 | 8.9 | 14.4 | 0.0 | 4.1 | 13.6 | 18.2  |
|  Lower 95% CI | 0.0 | 1.2 | 6.0 | 10.8 | NA | 2.0 | 9.9 | 14.1  |
|  Upper 95% CI | 2.1 | 4.7 | 11.8 | 18.0 | NA | 6.2 | 17.3 | 22.3  |
|  *0 = 0-29 days, 1 = 30-182 days, 6 = 183-364 days, 12 ≥ 365 days. Cumulative probability of event estimate is based on the Kaplan-Meier method  |   |   |   |   |   |   |   |   |

![img-9.jpeg](img-9.jpeg)

**Figure 10: All-Cause Mortality Kaplan-Meier Event Rate – Modified Per Protocol Population – Worst Case Scenario**

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**Table 13: Primary Endpoint: All-Cause Mortality – Modified Per Protocol Population – Worst Case Scenario**

|  Interval Post Procedure (months)* | TAVR N=390 |   |   |   | SAVR N=357  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  0 | 1 | 6 | 12 | 0 | 1 | 6 | 12  |
|  # at start of interval | 372 | 361 | 337 | 313 | 341 | 328 | 295 | 280  |
|  # events in interval | 11 | 24 | 24 | 20 | 13 | 33 | 15 | 15  |
|  # event cumulative | 11 | 35 | 59 | 79 | 13 | 46 | 61 | 76  |
|  K-M Event Rate | 1.1 | 3.2 | 9.4 | 16.1 | 0.0 | 4.1 | 13.5 | 17.9  |
|  Lower 95% CI | 0.0 | 1.4 | 6.4 | 12.4 | NA | 2.0 | 9.9 | 13.8  |
|  Upper 95% CI | 2.1 | 5.0 | 12.4 | 19.9 | NA | 6.2 | 17.1 | 22.0  |
|  *0 = 0-29 days, 1 = 30-182 days, 6 = 183-364 days, 12 ≥ 365 days. Cumulative probability of event estimate is based on the Kaplan-Meier method For worst case scenario the following assumptions were made for the censored subjects: the 7 TAVR subjects were assumed to have died on date of censoring and the 15 SAVR subjects were assumed to be alive at 1 year.  |   |   |   |   |   |   |   |   |

### 3. Key Secondary Safety and Effectiveness Endpoints

#### *Hierarchical Testing of Secondary Endpoints*

Hypothesis testing was performed on six pre-specified secondary endpoints using a hierarchical test procedure, as shown in Table 14. TAVR was found to be statistically non-inferior to SAVR within the pre-specified non-inferiority margins in terms of changes in mean gradient and EOA as well as in NYHA functional classification and KCCQ from baseline to 12 months. However, TAVR was not found to be statistically superior to SAVR with respect to the MACCE rate (p=0.1033), which was a powered secondary endpoint, as discussed in more detail later. In other words, the powered secondary endpoint of MACCE rate was not met. As a result, no hypothesis testing was conducted on SF-12 per the pre-specified hierarchical testing protocol.

**Table 14: Secondary Endpoints: Hierarchical Testing**

|  Secondary Objective | TAVR | SAVR | Difference (TAVR-SAVR) | Confidence Limit of the Difference | p-value | Test Result  |
| --- | --- | --- | --- | --- | --- | --- |
|  **Implanted Population**  |   |   |   |   |   |   |
|  #9 / Mean gradient change (12 Month – Baseline; mmHg) Ha: TAVR > SAVR-15 95% Lower CI | 39.04 ± 13.63 (n=290) | 35.42 ± 15.42 (n=222) | 3.62 | 1.49 | <0.0001 | Passed  |
|  #9 / EOA change (12 Month – Baseline; cm^{2}) Ha: TAVR > SAVR-0.375 95% Lower CI | 1.20 ± 0.53 (n=253) | 0.81 ± 0.50 (n=182) | 0.39 | 0.31 | <0.0001 | Passed  |
|  **AT Population**  |   |   |   |   |   |   |
|  #5 / NYHA change (12 Month – Baseline) Ha: TAVR > SAVR-0.375 95% Lower CI | 1.46 ± 0.76 (n=305) | 1.46 ± 0.81 (n=232) | -0.001 | -0.11 | <0.0001 | Passed  |

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|  Secondary Objective | TAVR | SAVR | Difference (TAVR-SAVR) | Confidence Limit of the Difference | p-value | Test Result  |
| --- | --- | --- | --- | --- | --- | --- |
|  #8 / KCCQ change (12 Month – Baseline) Ha: TAVR > SAVR-5 95% Lower CI | 23.20 ± 25.56 (n=243) | 21.88 ± 26.57 (n=189) | 1.32 | -2.84 | 0.0063 | Passed  |
|  Powered Secondary #1 / MACCE event rate at 1 Month (K-M) Ha: TAVR < SAVR 97.5% Upper CI | 8.21% (n=390) | 10.93% (n=357) | -2.73% | 1.51% | 0.1033 | Failed  |
|  #8 / SF-12 change (1 Month – Baseline) Ha: TAVR ≠ SAVR 95% two-sided CI | 4.91 ± 10.26 (n=215) | -0.12 ± 10.04 (n=158) | 5.03 | ( 2.94, 7.13) | NA | Not Tested  |
|  Plus-minus values present the mean ± standard deviation.  |   |   |   |   |   |   |

### *Powered Secondary Hypothesis*

For the AT population, the MACCE rate was 8.21% for TAVR and 10.93% for SAVR (p = 0.1033). The null hypothesis that TAVR was equal to SAVR in the MACCE rate could not be rejected. Of note is that the MACCE rate observed in the trial for SAVR was considerably lower than that assumed in the power calculation (20% vs. 12.1%), which resulted in the pre-specified sample size being too small to detect a difference between the two study arms even if a difference exists. Therefore, this particular secondary endpoint was underpowered for the specified hypothesis testing.

### *Adverse Events that Occurred in the PMA Clinical Study*

Table 15 provides a summary of the adverse events (AEs) that occurred in this study for the TAVR and SAVR treatment arms.

**Table 15: Adverse Event Summary – As Treated Population**

|  Event | 0-30 Days |   |   |   | 0-12 Months  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  TAVR N=390 |   | SAVR N=357 |   | TAVR N=390 |   | SAVR N=357  |   |
|   |  # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%)  |
|  **All-Cause Mortality** | 13 (13) | 3.3% | 16 (16) | 4.5% | 55 (55) | 14.2% | 67 (67) | 19.1%  |
|  Cardiovascular | 12 (12) | 3.1% | 16 (16) | 4.5% | 40 (40) | 10.4% | 44 (44) | 12.8%  |
|  Valve-Related^{1} | 9 (9) | 2.3% | 2 (2) | 0.6% | 21 (21) | 5.6% | 7 (7) | 2.2%  |
|  Non-Cardiovascular | 1 (1) | 0.3% | 0 (0) | 0.0% | 15 (15) | 4.2% | 23 (23) | 7.3%  |
|  **Reintervention** | 3 (3) | 0.8% | 0 (0) | 0.0% | 7 (7) | 1.9% | 0 (0) | 0.0%  |
|  Surgical | 2 (2) | 0.5% | 0 (0) | 0.0% | 3 (3) | 0.8% | 0 (0) | 0.0%  |
|  Percutaneous | 1 (1) | 0.3% | 0 (0) | 0.0% | 4 (4) | 1.1% | 0 (0) | 0.0%  |

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|  Event | 0-30 Days |   |   |   | 0-12 Months  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  TAVR N=390 |   | SAVR N=357 |   | TAVR N=390 |   | SAVR N=357  |   |
|   |  # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%)  |
|  **All Stroke** | 19 (20) | 4.9% | 22 (23) | 6.2% | 33 (34) | 8.8% | 42 (45) | 12.6%  |
|  Major Stroke | 15 (16) | 3.9% | 11 (11) | 3.1% | 22 (23) | 5.8% | 23 (23) | 7.0%  |
|  Minor Stroke | 4 (4) | 1.0% | 12 (12) | 3.4% | 11 (11) | 3.0% | 20 (22) | 6.0%  |
|  **All-Cause Mortality or Major Stroke** | 23 (29) | 5.9% | 24 (27) | 6.7% | 63 (78) | 16.3% | 79 (90) | 22.5%  |
|  **CEC Adjudicated Bleed^{2, 6}** | 150 (161) | 38.5% | NA | NA | 160 (186) | 41.2% | NA | NA  |
|  Life Threatening or Disabling | 48 (53) | 12.3% | NA | NA | 59 (65) | 15.3% | NA | NA  |
|  Major Bleed | 106 (108) | 27.3% | NA | NA | 110 (121) | 28.4% | NA | NA  |
|  **Re-Classified Bleed^{3}** | 157 (170) | 40.3% | 243 (258) | 68.1% | 167 (195) | 43.0% | 252 (290) | 70.8%  |
|  'Life Threatening or Disabling' | 53 (58) | 13.6% | 125 (130) | 35.0% | 64 (70) | 16.6% | 136 (150) | 38.4%  |
|  'Major Bleed' | 109 (112) | 28.1% | 123 (128) | 34.5% | 114 (125) | 29.5% | 130 (140) | 36.7%  |
|  **Major Vascular Complication** | 23 (23) | 5.9% | 6 (6) | 1.7% | 24 (24) | 6.2% | 7 (7) | 2.0%  |
|  **Acute Kidney Injury** | 23 (23) | 6.0% | 54 (54) | 15.1% | 23 (23) | 6.0% | 54 (54) | 15.1%  |
|  **MI** | 3 (3) | 0.8% | 3 (3) | 0.8% | 7 (7) | 1.9% | 5 (5) | 1.5%  |
|  Peri-Procedural | 3 (3) | 0.8% | 2 (2) | 0.6% | 3 (3) | 0.8% | 2 (2) | 0.6%  |
|  Spontaneous | 0 (0) | 0.0% | 1 (1) | 0.3% | 4 (4) | 1.1% | 3 (3) | 0.9%  |
|  **Cardiac Perforation** | 5 (5) | 1.3% | 0 (0) | 0.0% | 5 (5) | 1.3% | 0 (0) | 0.0%  |
|  **Cardiogenic Shock** | 9 (9) | 2.3% | 11 (11) | 3.1% | 9 (9) | 2.3% | 11 (11) | 3.1%  |
|  **Cardiac Tamponade** | 6 (6) | 1.5% | 4 (4) | 1.1% | 7 (7) | 1.8% | 5 (5) | 1.4%  |
|  **Valve Endocarditis** | 0 (0) | 0.0% | 0 (0) | 0.0% | 2 (2) | 0.6% | 4 (4) | 1.4%  |
|  **Valve Thrombosis** | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0%  |
|  **Valve Embolism/Device Migration** | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0%  |
|  **MACCE^{4}** | 30 (39) | 7.7% | 37 (42) | 10.4% | 79 (103) | 20.4% | 96 (117) | 27.3%  |
|  **MAE^{5, 6}** | 200 (311) | 51.3% | NA | NA | 229 (417) | 58.8% | NA | NA  |
|  **Aortic Valve Hospitalization** | 15 (15) | 3.9% | 18 (19) | 5.2% | 59 (85) | 16.1% | 43 (59) | 13.5%  |

$^{1}$ Valve-related death is any death caused by prosthetic valve dysfunction, valve thrombosis, embolism, bleeding event, or implanted valve endocarditis or related to reintervention on the operated valve.

$^{2}$ For TAVR, periprocedural transfusions meeting VARC I major and life-threatening bleeding criteria were adjudicated as events by the CEC irrespective of whether an overt bleeding complication had occurred. Since peri-procedural transfusions meeting VARC I criteria may be considered standard of care for SAVR procedures depending on the clinical circumstances, the same criteria were not applied and evidence of an overt bleeding complication (in addition to units transfused) were required to adjudicate an event for SAVR only. This makes a direct comparison of the CEC adjudicated bleeding rates in the trial inappropriate. For this reason, CEC adjudicated bleeding complications are shown for TAVR only.

$^{3}$ For the transfusion-based reclassification of bleeding events, units transfused were summed during the procedure, on the day of the procedure and the day following the procedure. Patients who received 2-3 units of packed red blood cells or homologous whole blood were considered to have had a 'major bleeding complication' and patients receiving ≥4 units were considered to have had a 'life-threatening or disabling bleeding complication' for both TAVR and SAVR. The nomenclature of the original adjudication was applied for consistency with this transfusion based re-classification.

$^{4}$ MACCE includes all-cause death, myocardial infarction (MI), all stroke, and reintervention.

$^{5}$ MAE includes all death, MI, all stroke, reintervention, cardiac perforation, cardiac tamponade, cardiogenic shock, valve embolism/device migration, prosthetic valve dysfunction, acute kidney injury, major vascular complication, life threatening of disabling bleed, major bleed, valve endocarditis VARC I Definitions.

$^{6}$ Bleeding complications and MAE rate cells have been intentionally left blank for SAVR in this table because of differing definitions employed for bleeding complications have made comparison of the rates to TAVR inappropriate.

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### Neurological Events

Table 16 provides a summary of the neurological events that occurred in this study for the TAVR and SAVR treatment arms. Stroke and TIA were defined according to the Valve Academic Research Consortium I (VARC-I) definitions.$^{[1]}$

**Table 16: CEC Adjudicated Neurological Events – As Treated Population**

|  Event | 0-30 Days |   |   |   | 0-12 Months  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  TAVR N=390 |   | SAVR N=357 |   | TAVR N=390 |   | SAVR N=357  |   |
|   |  # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%)  |
|  **Neurological Events** | 56 (61) | 14.5% | 79 (90) | 22.2% | 79 (101) | 20.8% | 110 (133) | 31.9%  |
|  All Stroke | 19 (20) | 4.9% | 22 (23) | 6.2% | 33 (34) | 8.8% | 42 (45) | 12.6%  |
|  Major Stroke | 15 (16) | 3.9% | 11 (11) | 3.1% | 22 (23) | 5.8% | 23 (23) | 7.0%  |
|  Ischemic | 14 (14) | 3.6% | 9 (9) | 2.5% | 19 (19) | 5.0% | 18 (18) | 5.5%  |
|  Hemorrhagic | 1 (2) | 0.3% | 0 (0) | 0.0% | 3 (4) | 0.8% | 3 (3) | 0.9%  |
|  Undetermined | 0 (0) | 0.0% | 2 (2) | 0.6% | 0 (0) | 0.0% | 2 (2) | 0.6%  |
|  Minor Stroke | 4 (4) | 1.0% | 12 (12) | 3.4% | 11 (11) | 3.0% | 20 (22) | 6.0%  |
|  Ischemic | 3 (3) | 0.8% | 11 (11) | 3.1% | 10 (10) | 2.7% | 18 (20) | 5.4%  |
|  Hemorrhagic | 0 (0) | 0.0% | 1 (1) | 0.3% | 0 (0) | 0.0% | 2 (2) | 0.6%  |
|  Undetermined | 1 (1) | 0.3% | 0 (0) | 0.0% | 1 (1) | 0.3% | 0 (0) | 0.0%  |
|  TIA | 3 (3) | 0.8% | 1 (1) | 0.3% | 6 (7) | 1.6% | 5 (5) | 1.6%  |
|  Encephalopathy | 36 (38) | 9.4% | 61 (66) | 17.2% | 49 (57) | 13.0% | 69 (81) | 19.7%  |
|  Cerebral Infarction- Asymptomatic | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0%  |
|  Intracranial Hemorrhage | 0 (0) | 0.0% | 0 (0) | 0.0% | 3 (3) | 0.9% | 2 (2) | 0.7%  |

### Echocardiographic Assessment of Total Aortic Regurgitation

Table 17 summarizes the total aortic regurgitation (AR) severity over time in the TAVR and SAVR treatment arms.

**Table 17: Total Aortic Regurgitation by Visit (Core Lab) – Implanted Population**

|  Interval / Valve Size | All TAVR N=389 | All SAVR N=353  |
| --- | --- | --- |
|  **Screening/ Baseline** |  |   |
|  None | 15.1% (58/385) | 14.7% (51/346)  |
|  Trace | 37.9% (146/385) | 33.2% (115/346)  |
|  Mild | 41.8% (161/385) | 46.0% (159/346)  |
|  Moderate | 5.2% (20/385) | 5.5% (19/346)  |
|  Severe | 0.0% (0/385) | 0.6% (2/346)  |
|  **1 Month** |  |   |
|  None | 12.3% (44/359) | 65.3% (201/308)  |
|  Trace | 41.2% (148/359) | 22.7% (70/308)  |
|  Mild | 36.5% (131/359) | 10.7% (33/308)  |
|  Moderate | 8.1% (29/359) | 1.3% (4/308)  |
|  Severe | 1.9% (7/359) | 0.0% (0/308)  |

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|  Interval / Valve Size | All TAVR N=389 | All SAVR N=353  |
| --- | --- | --- |
|  **6 Month** |  |   |
|  None | 21.4% (68/318) | 60.3% (152/252)  |
|  Trace | 37.4% (119/318) | 28.2% (71/252)  |
|  Mild | 29.9% (95/318) | 9.9% (25/252)  |
|  Moderate | 9.7% (31/318) | 1.6% (4/252)  |
|  Severe | 1.6% (5/318) | 0.0% (0/252)  |
|  **12 Month** |  |   |
|  None | 28.6% (85/297) | 68.2% (152/223)  |
|  Trace | 35.4% (105/297) | 21.5% (48/223)  |
|  Mild | 29.0% (86/297) | 9.0% (20/223)  |
|  Moderate | 6.7% (20/297) | 0.9% (2/223)  |
|  Severe | 0.3% (1/297) | 0.4% (1/223)  |

### *Echocardiographic Assessment of EOA and Mean Gradient*

The EOA and the mean gradient values obtained over time for the TAVR and SAVR patients in the Implanted population are shown in Table 18.

**Table 18: Effective Orifice Area (cm$^{2}$) & Mean Gradient (mmHg) By Visit (Core Lab) – Implanted Population**

|   | EOA (cm^{2}) |   | Mean Gradient (mmHg)  |   |
| --- | --- | --- | --- | --- |
|   |  TAVR N=389 | SAVR N=353 | TAVR N=389 | SAVR N=353  |
|  **Screening/Baseline** | 0.72 ± 0.23 (349) | 0.73 ± 0.24 (306) | 48.27 ± 15.31 (387) | 47.65 ± 13.85 (350)  |
|  **1 Month** | 1.95 ± 0.56 (344) | 1.60 ± 0.51 (280) | 8.88 ± 3.87 (356) | 11.71 ± 5.71 (311)  |
|  **6 Month** | 1.91 ± 0.53 (293) | 1.57 ± 0.49 (226) | 9.05 ± 4.07 (318) | 12.11 ± 6.32 (253)  |
|  **12 Month** | 1.91 ± 0.51 (274) | 1.57 ± 0.49 (206) | 9.07 ± 3.49 (291) | 12.40 ± 7.38 (224)  |
|  Plus-minus values present the mean ± standard deviation.  |   |   |   |   |

### *Conduction Disturbance Requiring Permanent Pacemaker Implantation*

Table 19 presents the pacemaker implantation rate for the TAVR and SAVR patients in the AT population. Table 20 summarizes subjects with key measurements on the screening electrocardiogram and subsequent rate of new permanent pacemaker implantation (PPI) at 30 days in these subjects. Subjects with pre-existing right bundle branch block (RBBB) and atrioventricular block (AVB) experienced higher PPI post CoreValve implant; however due to the limited sample size, limited conclusions can be developed. Additionally, no conclusions can be developed for subjects with pre-existing right bundle branch block (LBBB) due to the limited sample size. These variables are consistent with results from literature. De Carlo et al. evaluated 275 consecutive patients with no prior history of PPI and underwent a CoreValve implantation.$^{[2]}$ Using univariate analyses, patients with longer PR interval, longer QRS duration or RBBB at baseline were identified as having significantly higher PPI rate than those without. Furthermore, using multivariate analyses, baseline RBBB and longer PR interval were identified as independent predictors of PPI.

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**Table 19: Conduction Disturbance Requiring Pacemaker – As Treated Population**

|   | TAVR N=390 |   | SAVR N=357  |   |
| --- | --- | --- | --- | --- |
|   |  # of Patients | K-M Event Rate (%) | # of Patients | K-M Event Rate (%)  |
|  **New Permanent Pacemaker Implant^{1}**  |   |   |   |   |
|  0-30 Days | 76 | 19.8% | 25 | 7.1%  |
|  0-12 Months | 85 | 22.3% | 38 | 11.3%  |
|  **Permanent Pacemaker Implant^{2}**  |   |   |   |   |
|  0-30 Days | 76 | 25.7% | 24 | 8.6%  |
|  0-12 Months | 84 | 28.6% | 36 | 13.5%  |
|  ^{1} Patients with pacemaker or ICD at baseline are included in the denominator.  |   |   |   |   |
|  ^{2} Patients with pacemaker or ICD at baseline are excluded from the numerator and denominator. Note one (1) TAVR patient and two (2) SAVR patients with baseline pacemaker/ICD, received new pacemaker/ICD between 30-365 days.  |   |   |   |   |

**Table 20: Site Reported Screening Electrocardiogram and Rate of New Permanent Pacemaker Implantation (PPI) at 30 Days (High Risk TAVR AT subjects without Pre-Existing IPG/ICD)**

|  Measurement | PPI (%)  |   |
| --- | --- | --- |
|   |  Present at Screening | Not Present at Screening  |
|  **PR Interval (ms)**  |   |   |
|  PR <200 | 21.97% ( 38/173) |   |
|  PR >=200 | 30.77% ( 24/78) |   |
|  **Ventricular Conduction Delays**  |   |   |
|  LBBB | 16.00% ( 4/ 25) | 26.39% ( 71/269)  |
|  RBBB | 63.64% ( 28/ 44) | 18.80% ( 47/250)  |
|  **AtrioVentricular Block**  |   |   |
|  AVB | 32.84% ( 22/ 67) | 23.28% ( 54/232)  |
|  1^{st} Degree | 30.36% ( 17/ 56) |   |
|  2^{nd} Degree |  |   |
|  MOBITZ I |  |   |
|  MOBITZ II |  |   |
|  3^{rd} Degree |  |   |
|  Other | 45.45% ( 5/ 11) |   |

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# Ratio of Days Alive out of Hospital versus Total Days Alive

The ratio of days alive out of hospital to total days alive was compared at 12 months between TAVR and SAVR patients (Table 21). All hospitalizations, including the hospital stays for device implantations, were analyzed. The ratio was 0.92 ± 0.20 for TAVR and 0.88 ± 0.23 for SAVR, which can be interpreted as follows: on average TAVR patients spent 92% and SAVR patients spent 88% of days alive after procedure out of the hospital.

**Table 21: Ratio of Days Alive Out of Hospital – As Treated Population**

|   | TAVR N=390 | SAVR N=357  |
| --- | --- | --- |
|  Total Number of Days Followed (Alive) | 331.1 ± 91.8 | 310.1 ± 111.7  |
|  Number of Days in Hospital | 12.7 ± 14.5 | 16.3 ± 14.0  |
|  Ratio Days Alive and Out of Hospital | 0.92 ± 0.20 | 0.88 ± 0.23  |
|  Plus-minus values present the mean ± standard deviation.  |   |   |

# NYHA Functional Class

The NYHA classification was evaluated at several time points through the first year of follow-up, as shown in Table 22.

**Table 22: NYHA Classification By Visit – As Treated Population**

|  NYHA Classification | TAVR N=390 | SAVR N=357  |
| --- | --- | --- |
|  **Baseline**  |   |   |
|  NYHA I | 0.0% (0/390) | 0.0% (0/350)  |
|  NYHA II | 16.9% (66/390) | 18.3% (64/350)  |
|  NYHA III | 69.7% (272/390) | 66.3% (232/350)  |
|  NYHA IV | 13.3% (52/390) | 15.4% (54/350)  |
|  Died prior to visit | 0.0% (0/390) | 0.0% (0/350)  |
|  Exit prior to visit | 0 | 0  |
|  Visit occurred but NYHA not obtained | 0 | 7  |
|  Visit missed | 0 | 0  |
|  **1 Month**  |   |   |
|  NYHA I | 43.4% (163/376) | 32.6% (108/331)  |
|  NYHA II | 39.4% (148/376) | 40.8% (135/331)  |
|  NYHA III | 13.0% (49/376) | 18.4% (61/331)  |
|  NYHA IV | 0.3% (1/376) | 4.2% (14/331)  |
|  Died prior to visit | 4.0% (15/376) | 3.9% (13/331)  |
|  Exit prior to visit | 0 | 1  |
|  Visit occurred but NYHA not obtained | 7 | 10  |
|  Visit missed | 7 | 15  |

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|  NYHA Classification | TAVR N=390 | SAVR N=357  |
| --- | --- | --- |
|  **12 Month** |  |   |
|  NYHA I | 48.2% (176/365) | 44.1% (134/304)  |
|  NYHA II | 30.7% (112/365) | 28.3% (86/304)  |
|  NYHA III | 4.7% (17/365) | 4.6% (14/304)  |
|  NYHA IV | 0.0% (0/365) | 0.7% (2/304)  |
|  Died prior to visit | 16.4% (60/365) | 22.4% (68/304)  |
|  Exit prior to visit | 2 | 8  |
|  Visit occurred but NYHA not obtained | 15 | 27  |
|  Visit missed | 5 | 18  |

### *QoL Change*

The QoL changes from baseline at 30 days and 12 months were evaluated using the Kansas City Cardiomyopathy Questionnaire (KCCQ), the QualityMetric's SF-12v2® Health Survey (SF12), and the EuroQoL (EQ-5D), as shown in Tables 23 - 25 for the TAVR and SAVR cohorts.

The KCCQ is a validated self-administered 23-item questionnaire that quantifies physical limitations, symptoms, self-effectiveness, social interference and quality of life. These individual scales are incorporated into an Overall Summary Score which combines the domains of physical limitation, symptoms, QoL, and social limitation with values ranging from 0-100; higher scores indicate lesser symptoms and better quality of life. Previous studies have suggested that KCCQ Overall Summary scores correlate roughly with New York Heart Association Functional Class as follows: Class I ≈ KCCQ Summary Score 75-100; Class II ≈ 60-74; Class III ≈ 45-59; and Class IV ≈ 0-44. In addition, there is a Clinical Summary Score that combines the domains of physical limitation and symptoms.

SF12 is a shorter version of the SF-36v2® Health Survey that uses 12 questions to measure functional health and well-being from the patient's point of view and is generally reported in two summary scores which evaluate physical (the SF-12 Physical Summary Score) and mental (the SF-12 Mental Summary Score) health. Values range from 0-100; higher scores indicate better functional health and well-being.

The EQ-5D is a measure of self-reported health outcomes that is applicable to a wide range of health conditions and treatments. It consists of 2 parts: a descriptive system (Part I) and a visual analogue scale (Part II). Part I of the scale consists of 5 single-item dimensions including: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has a 3 point response scale designed to indicate the level of the problem. The overall EQ-5D score from Part I is evaluated on a scale where 0.0 = death and 1.0 = perfect health. Part II uses a vertical graduated visual analogue scale (thermometer) to measure health status, ranging from worst imaginable health state to best imaginable health state.

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FDA cautions interpretation of these results in the setting of an unblinded trial, particularly in a comparison of patients undergoing open heart surgery versus patients receiving less invasive TAVR.

Table 23: KCCQ By Visit – As Treated Population

|  KCCQ | TAVR N=390 | SAVR N=357  |
| --- | --- | --- |
|  **Baseline** |  |   |
|  Overall Summary Score | 46.9 ± 23.4 | 46.6 ± 22.3  |
|  Clinical Summary Score | 51.4 ± 23.3 | 50.8 ± 22.3  |
|  **1 Month** |  |   |
|  Overall Summary Score | 66.2 ± 24.1 | 51.6 ± 25.4  |
|  Change from Baseline | 19.0 ± 29.4 | 3.7 ± 27.6  |
|  Clinical Summary Score | 66.8 ± 23.5 | 54.8 ± 24.5  |
|  Change from Baseline | 14.8 ± 28.6 | 2.2 ± 26.6  |
|  **12 Months** |  |   |
|  Overall Summary Score | 72.1 ± 21.8 | 70.5 ± 22.1  |
|  Change from Baseline | 23.2 ± 25.6 | 21.9 ± 26.6  |
|  Clinical Summary Score | 69.9 ± 22.1 | 68.3 ± 22.2  |
|  Change from Baseline | 16.7 ± 25.7 | 15.3 ± 26.1  |
|  Plus-minus values present the mean ± standard deviation.  |   |   |

Table 24: SF12 By Visit – As Treated Population

|  SF-12 | TAVR N=390 | SAVR N=357  |
| --- | --- | --- |
|  **Baseline** |  |   |
|  Physical Component | 30.8 ± 9.2 | 31.0 ± 8.6  |
|  Mental Component | 47.5 ± 12.1 | 48.4 ± 11.7  |
|  **1 Month** |  |   |
|  Physical Component | 35.9 ± 9.5 | 31.7 ± 8.5  |
|  Change from Baseline | 4.9 ± 10.3 | -0.1 ± 10.0  |
|  Mental Component | 51.1 ± 11.1 | 45.0 ± 13.1  |
|  Change from Baseline | 2.6 ± 13.1 | -2.5 ± 13.4  |
|  **12 Months** |  |   |
|  Physical Component | 37.0 ± 11.2 | 36.9 ± 9.7  |
|  Change from Baseline | 6.0 ± 11.6 | 5.2 ± 10.3  |
|  Mental Component | 52.8 ± 10.8 | 52.5 ± 10.5  |
|  Change from Baseline | 4.5 ± 11.9 | 3.2 ± 12.1  |
|  Plus-minus values present the mean ± standard deviation.  |   |   |

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**Table 25: EQ-5D By Visit – As Treated Population**

|  EQ-5D | TAVR N=390 | SAVR N=357  |
| --- | --- | --- |
|  **Baseline** |  |   |
|  Index Score | 0.73 ± 0.20 | 0.73 ± 0.18  |
|  **1 Month** |  |   |
|  Index Score | 0.78 ± 0.19 | 0.67 ± 0.25  |
|  Change from Baseline | 0.04 ± 0.24 | -0.07 ± 0.26  |
|  **12 Months** |  |   |
|  Index Score | 0.78 ± 0.18 | 0.78 ± 0.18  |
|  Change from Baseline | 0.04 ± 0.20 | 0.01 ± 0.19  |
|  Plus-minus values present the mean ± standard deviation.  |   |   |

#### 4. Additional Study Observations

##### *Procedure Data*

As recommended in the protocol, the procedure was to occur within 30 days of randomization. As such, time to procedure was calculated between the randomization date and the date for the first attempted procedure. It was 13.1 ± 10.9 days for TAVR patients and 18.1 ± 14.3 days for SAVR patients.

Table 26 provides a summary of the procedure data for the TAVR cohort. The mean total time in the catheterization laboratory or operating room was approximately 3.5 hours for patients in the iliofemoral cohort, while the mean total procedure time (skin-to-skin) was on average slightly greater than 1 hour. In comparison, the mean total time in the catheterization laboratory or operating room was approximately 4 hours for the non-iliofemoral cohort, while the mean total procedure time was slightly less than 1 hour.

**Table 26: TAVR Procedure Data - As Treated Population**

|   | TAVR IF N=323 | TAVR NIF N=67 | TAVR N=390  |
| --- | --- | --- | --- |
|  **Number of Index Procedures^{1}** | 323 | 66 | 389  |
|  Total Time in Cath Lab or OR (min) | 209.6 ± 58.6 | 249.1 ± 63.4 | 216.3 ± 61.2  |
|  Total Procedure Time (min) | 61.4 ± 33.9 | 55.6 ± 41.7 | 60.4 ± 35.3  |
|  Total CoreValve Delivery Time (min) | 13.5 ± 11.3 | 15.4 ± 13.4 | 13.8 ± 11.7  |
|  **Number of Valves Used** |  |  |   |
|  0^{2} | 0.0% (0/323) | 1.5% (1/67) | 0.3% (1/390)  |
|  1 | 91.3% (295/323) | 92.5% (62/67) | 91.5% (357/390)  |
|  2 | 8.4% (27/323) | 6.0% (4/67) | 7.9% (31/390)  |
|  3 | 0.3% (1/323) | 0.0% (0/67) | 0.3% (1/390)  |
|  **Number of Valves Implanted** |  |  |   |
|  0 | 0.0% (0/323) | 1.5% (1/67) | 0.3% (1/390)  |
|  1 | 95.0% (307/323) | 98.5% (66/67) | 95.6% (373/390)  |
|  2 | 5.0% (16/323) | 0.0% (0/67) | 4.1% (16/390)  |
|  3 | 0.0% (0/323) | 0.0% (0/67) | 0.0% (0/390)  |

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|   | TAVR IF N=323 | TAVR NIF N=67 | TAVR N=390  |
| --- | --- | --- | --- |
|  **Valve Size Implanted** |  |  |   |
|  23 mm | 1.5% (5/323) | 1.5% (1/66) | 1.5% (6/389)  |
|  26 mm | 29.4% (95/323) | 40.9% (27/66) | 31.4% (122/389)  |
|  29 mm | 49.5% (160/323) | 48.5% (32/66) | 49.4% (192/389)  |
|  31 mm | 19.5% (63/323) | 9.1% (6/66) | 17.7% (69/389)  |
|  Device Success^{3} | 86.9% (273/314) | 87.3% (55/63) | 87.0% (328/377)  |
|  Procedure Success^{4} | 81.5% (260/319) | 82.8% (53/64) | 81.7% (313/383)  |

$^{1}$ The table includes patients with the index procedure. Index procedure (TAVR): the first procedure that the Medtronic CoreValve system delivery catheter is introduced.

$^{2}$ A single patient had no valves used or implanted during the procedure as the patient became hypotensive after the TEE probe was placed and the patient was converted to SAVR.

$^{3}$ Device success is defined as deployment, only 1 valve implanted, only 1 valve in correct anatomic location, EOA >1.2cm$^{2}$ for 26, 29 and 31mm and ≥ 0.9 cm$^{2}$ for 23mm, mean gradient < 20mmHg or peak velocity < 3 m/sec, and aortic regurgitation < moderate.

$^{4}$ Procedure success is defined as device success and absence of in-hospital MACCE.

### *Valve-in-Valve Experience*

In the “As Treated” population, a total of 16 patients had more than one CoreValve devices implanted. Fourteen (14) patients had a CoreValve-in-CoreValve procedure, all of which were due to device malpositioning and/or residual aortic regurgitation. Two (2) patients had a non valve-in-valve implant of a second valve (i.e., the first CoreValve was placed in the aorta).

### *Results by Access Routes - Iliofemoral (IF) and Non-Iliofemoral (NIF) Cohorts*

#### **Primary Endpoint Stratified by Access Route**

The study was powered to demonstrate non-inferiority of TAVR compared to SAVR for the primary endpoint for all patients (iliofemoral and non-iliofemoral) pooled. It was pre-specified that the primary endpoint would be assessed for different access route subgroups independently, but this assessment was not powered and would not be the basis for assessing success or failure of the primary endpoint. The all-cause mortality rates are shown in Figure 11 and Table 27 for the iliofemoral subgroup and Figure 12 and Table 28 for the non-iliofemoral subgroup.

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![img-10.jpeg](img-10.jpeg)

Figure 11: All-Cause Mortality – Iliofemoral As Treated Population

Table 27: All-Cause Mortality – Iliofemoral As Treated Population

|  Interval Post Procedure (months)* | TAVR N=390 |   |   |   | SAVR N=357  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  0 | 1 | 6 | 12 | 0 | 1 | 6 | 12  |
|  # at start of interval | 323 | 312 | 297 | 275 | 300 | 287 | 249 | 235  |
|  # events in interval | 11 | 14 | 17 | 19 | 12 | 30 | 10 | 16  |
|  # event cumulative | 11 | 25 | 42 | 61 | 12 | 42 | 52 | 68  |
|  K-M Event Rate | 1.2 | 3.4 | 7.8 | 13.4 | 0.0 | 4.3 | 14.1 | 17.6  |

*0 = 0-29 days, 1 = 30-182 days, 6 = 183-364 days, 12 ≥ 365 days.
Cumulative probability of event estimate is based on the Kaplan-Meier method

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![img-11.jpeg](img-11.jpeg)

**Figure 12: All-Cause Mortality – Non-Iliofemoral As Treated Population**

**Table 28: All-Cause Mortality – Non-Iliofemoral As Treated Population**

|  Interval Post Procedure (months)* | TAVR N=390 |   |   |   | SAVR N=357  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  0 | 1 | 6 | 12 | 0 | 1 | 6 | 12  |
|  # at start of interval | 67 | 65 | 56 | 54 | 57 | 54 | 48 | 39  |
|  # events in interval | 2 | 8 | 2 | 1 | 3 | 5 | 7 | 1  |
|  # event cumulative | 2 | 10 | 12 | 13 | 3 | 8 | 15 | 16  |
|  K-M Event Rate | 1.5 | 3.0 | 15.1 | 18.1 | 0.0 | 5.3 | 14.2 | 27.3  |
|  *0 = 0-29 days, 1 = 30-182 days, 6 = 183-364 days, 12 ≥ 365 days. Cumulative probability of event estimate is based on the Kaplan-Meier method  |   |   |   |   |   |   |   |   |

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### AEs Stratified by Access Route

The AEs for the iliofemoral patients and non-iliofemoral patients in both study arms are shown in Tables 29 and 30, respectively.

**Table 29: Adverse Event Summary – Iliofemoral As Treated Population**

|  Event | 0-30 Days |   |   |   | 0-12 Months  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  TAVR N=323 |   | SAVR N=300 |   | TAVR N=323 |   | SAVR N=300  |   |
|   |  # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%) | # Pts (#Event) | K-M Rate (%)  |
|  **All-Cause Mortality** | 11 (11) | 3.4% | 13 (13) | 4.3% | 43 (43) | 13.4% | 52 (52) | 17.6%  |
|  Cardiovascular | 10 (10) | 3.1% | 13 (13) | 4.3% | 32 (32) | 10.1% | 35 (35) | 12.0%  |
|  Valve-Related^{1} | 8 (8) | 2.5% | 1 (1) | 0.3% | 18 (18) | 5.7% | 4 (4) | 1.5%  |
|  Non-Cardiovascular | 1 (1) | 0.3% | 0 (0) | 0.0% | 11 (11) | 3.7% | 17 (17) | 6.3%  |
|  **Reintervention** | 2 (2) | 0.6% | 0 (0) | 0.0% | 6 (6) | 2.0% | 0 (0) | 0.0%  |
|  Surgical | 1 (1) | 0.3% | 0 (0) | 0.0% | 2 (2) | 0.7% | 0 (0) | 0.0%  |
|  Percutaneous | 1 (1) | 0.3% | 0 (0) | 0.0% | 4 (4) | 1.3% | 0 (0) | 0.0%  |
|  **All Stroke** | 16 (17) | 5.0% | 15 (15) | 5.0% | 28 (29) | 9.0% | 30 (32) | 10.8%  |
|  Major Stroke | 12 (13) | 3.7% | 6 (6) | 2.0% | 18 (19) | 5.8% | 13 (13) | 4.7%  |
|  Minor Stroke | 4 (4) | 1.3% | 9 (9) | 3.0% | 10 (10) | 3.3% | 17 (19) | 6.2%  |
|  **CEC Adjudicated Bleed^{2, 6}** | 107 (112) | 33.1% | NA | NA | 117 (136) | 36.4% | NA | NA  |
|  Life Threatening or Disabling | 32 (34) | 9.9% | NA | NA | 42 (45) | 13.2% | NA | NA  |
|  Major Bleed | 76 (78) | 23.6% | NA | NA | 80 (91) | 25.0% | NA | NA  |
|  **Re-Classified Bleed^{3}** | 113 (119) | 35.0% | 204 (218) | 68.0% | 123 (143) | 38.3% | 210 (238) | 70.2%  |
|  'Life Threatening or Disabling' | 35 (37) | 10.8% | 105 (110) | 35.0% | 45 (48) | 14.1% | 113 (121) | 38.0%  |
|  'Major Bleed' | 80 (82) | 24.9% | 103 (108) | 34.4% | 85 (95) | 26.6% | 108 (117) | 36.2%  |
|  **Major Vascular Complication** | 21 (21) | 6.5% | 5 (5) | 1.7% | 22 (22) | 6.8% | 6 (6) | 2.0%  |
|  **Acute Kidney Injury** | 16 (16) | 5.0% | 43 (43) | 14.3% | 16 (16) | 5.0% | 43 (43) | 14.3%  |
|  **MI** | 3 (3) | 0.9% | 2 (2) | 0.7% | 7 (7) | 2.3% | 4 (4) | 1.4%  |
|  Peri-Procedural | 3 (3) | 0.9% | 2 (2) | 0.7% | 3 (3) | 0.9% | 2 (2) | 0.7%  |
|  Spontaneous | 0 (0) | 0.0% | 0 (0) | 0.0% | 4 (4) | 1.4% | 2 (2) | 0.8%  |
|  **Cardiac Perforation** | 4 (4) | 1.2% | 0 (0) | 0.0% | 4 (4) | 1.2% | 0 (0) | 0.0%  |
|  **Cardiogenic Shock** | 6 (6) | 1.9% | 8 (8) | 2.7% | 6 (6) | 1.9% | 8 (8) | 2.7%  |
|  **Cardiac Tamponade** | 5 (5) | 1.5% | 3 (3) | 1.0% | 6 (6) | 1.9% | 4 (4) | 1.3%  |
|  **Valve Endocarditis** | 0 (0) | 0.0% | 0 (0) | 0.0% | 2 (2) | 0.7% | 3 (3) | 1.2%  |
|  **Valve Thrombosis** | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0%  |
|  **Valve Embolism/Device Migration** | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0% | 0 (0) | 0.0%  |
|  **MACCE^{4}** | 26 (33) | 8.0% | 29 (30) | 9.7% | 65 (85) | 20.2% | 76 (88) | 25.6%  |
|  **MAE^{5, 6}** | 151 (239) | 46.7% | NA | NA | 177 (331) | 54.8% | NA | NA  |
|  **Aortic Valve Hospitalization** | 8 (8) | 2.5% | 11 (12) | 3.8% | 44 (68) | 14.5% | 30 (43) | 11.3%  |
|  **New Permanent Pacemaker Implant^{7}** | 64 (65) | 26.5% | 21 (21) | 9.0% | 70 (72) | 29.1% | 33 (33) | 14.9%  |

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|  Event | 0-30 Days |   |   |   | 0-12 Months  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  TAVR…

---

**Source:** [https://fda-staging.innolitics.com/device/P130021S002](https://fda-staging.innolitics.com/device/P130021S002)

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