Medtronic FR995-21 Instructions for Use

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Freestyle™

995 Bioprosthesis

Instructions for Use

Caution: Federal law (USA) restricts this device to sale by or on the order of a physician.

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Trademarks may be registered and are the property of their respective owners.

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Explanation of symbols on package labeling

Refer to the device labeling to see which symbols apply to this product.

Use-by date

Serial number

Do not reuse

Sterile LC: Device has been sterilized using liquid chemical sterilants according to EN/ISO 14160.

Temperature limitation

Size

For US audiences only

Catalog number

MR Safe

Authorized representative in the European Community

Manufacturer

Do not resterilize

Quantity

Nonpyrogenic

Do not use if indicator turns black

Manufactured in

Model

Date of manufacture

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Figure 1. Opening the valve container

Figure 2. Removing the retainer from the jar

Figure 3. Removing the cap from the valve retainer body

Figure 4. Removing the bioprosthesis from the retainer

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Figure 5. Releasing the identification tag (serial number)

Figure 6. Rinsing the bioprosthesis

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Bioprosthesis

1. Device description

The Freestyle™ bioprosthesis, Model 995, consists of a porcine aortic root preserved in buffered 0.2% glutaraldehyde with a thin polyester cloth covering added to strengthen the proximal (inflow) suture line and to cover any exposed porcine myocardium. The Freestyle bioprosthesis is treated with an alpha amino oleic acid antimineralization process, AOA™, which has been shown to mitigate porcine leaflet calcification in animal studies. The design of the Freestyle bioprosthesis allows the physician to trim the prosthesis for replacement using the subcoronary, full-root or root-inclusion technique. The Freestyle bioprostheses are available in the diameters and sizes shown in Table 1.

Table 1. Freestyle bioprosthesis, Model 995 available sizes and diameters

Size (mm) A

Outside diameter (+ 0.5 mm

- 0.0 mm)

19 19.0 30 3.0 21 21.0 32 3.0 23 23.0 32 3.0 25 25.0 34 3.0 27 27.0 34 3.0 29 29.0 39±3 mm 3.0

Profile height (± 2 mm)

Inner cloth height

(± 0.5 mm)

2. Indications for use

The Freestyle bioprosthesis is indicated for the replacement of malfunctioning native or prosthetic aortic valves with the option of aortic root replacement.

3. Contraindications

No contraindications for use of this device are known.

4. Warnings and precautions

4.1. Warnings

This device was designed for single patient use only. Do not reuse, reprocess, or resterilize this product. Reuse, reprocessing, or resterilization may compromise the structural integrity of the device or create a risk of contamination of the device, which could result in patient injury, illness, or death.

Check the shipping temperature indicator inside the carton. If the shipping temperature indicator window is black, the valve is not suitable for clinical use.

Do not resterilize the valve by any method. Exposure of the bioprosthesis and container to irradiation, steam, ethylene oxide or other chemical sterilants will render the bioprosthesis unfit for use.

Warning: Accelerated deterioration due to calcific degeneration of bioprostheses may occur in:

■

Children, adolescents, or young adults

■

Patients with altered calcium metabolism (for example, chronic renal failure, hyperparathyroidism)

4.2. Precautions

Implanting physicians must be familiar with the techniques for implanting an unstented bioprosthesis. These techniques are similar to those required for allograft implantation.

In vitro testing of the Freestyle bioprosthesis has only been performed in less compliant simulated aorta comparable to the aorta of middle aged or older patients. Data from clinical or in vitro testing are not available from more compliant simulated aorta comparable to the aorta of a younger patient.

Limited implant experience is available for the 19 mm bioprosthesis implanted with the root-inclusion technique (none), and with the full-root technique (5 patients): and for the 21 mm bioprosthesis implanted with the root-inclusion technique (3 patients) (section 6, Clinical Studies).

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4.2.1. Precautions prior to use

Do not use the bioprosthesis if:

■

The bioprosthesis has been dropped, damaged, or mishandled in any way

■

The Use-by date has elapsed

■

All tamper strips on the glass jar and lid container are damaged

■

The serial number tag does not match the container label

■

The shipping temperature indicator window has turned black

■

The glutaraldehyde storage solution does not completely cover the bioprosthesis

4.2.2. Precautions during use

■

Do not expose the bioprosthesis to solutions other than the storage solution in which it was shipped, the sterile isotonic saline solution used during the rinsing procedure, or the sterile isotonic saline used to irrigate the bioprosthesis.

■

Do not allow the tissue of the bioprosthesis to dry. Continuous submersion or irrigation is required (section 10.3 Handling and Preparation Instructions).

■

Do not add antibiotics to either the storage or the rinse solution. Do not apply antibiotics to the bioprosthesis.

■

Do not lacerate the leaflet tissue. If a valve is damaged, the valve must be explanted and replaced. Note: The leaflets of the Freestyle bioprosthesis are in an open position. Use extreme caution to avoid cutting or puncturing

the leaflets when tailoring and suturing the bioprosthesis.

■

Do not invert the valve. Inversion will damage valve tissue.

■

Passage of a catheter through any bioprosthesis may damage the valve and is, therefore, not recommended.

■

Trim suture ends close to the knot to prevent abrasion of leaflet tissue.

5. Adverse events

Original clinical study (19 mm, 21 mm, 23 mm, 25 mm, and 27 mm)

A prospective non-randomized multicenter international study evaluated the Freestyle bioprosthesis with patient follow-up out to 3 years. A total of 882 patients received the bioprosthesis. Patients were monitored throughout the entire postoperative period for possible adverse events. The cumulative follow-up was 1246 patient-years with a mean follow-up of 17 months (SD = 12 months, range = 0 to 42 months).

29 mm clinical study

A prospective non-randomized multicenter study evaluated the Freestyle bioprosthesis, 29 mm, with patient follow-up out to 1 year. A total of 37 patients received the 29 mm bioprosthesis. Patients were monitored throughout the entire postoperative period for possible adverse events. The cumulative follow-up was 21 patient-years with a mean follow-up of 8 months (SD = 6 months, range = 0 to 24 months).

Note: the total number of patients in this study data will reference 33 patients. (Four out of 37 patients did not meet study requirements.)

Ten year data

A prospective, multi-center, non-randomized, clinical study evaluated the long-term safety and effectiveness of the Freestyle bioprosthesis. A total of 725 patients received the bioprosthesis. Patients were monitored throughout the entire postoperative period for possible adverse events. The cumulative follow-up was 4487.6 patient-years with a mean follow-up of 6.2 years (SD=3.2 years, range 0 to 11.6 years).

5.1. Subcoronary technique

Original clinical study (19 mm, 21 mm, 23 mm, 25 mm, and 27 mm)

A total of 640 FREESTYLE Bioprostheses were implanted with the subcoronary technique in 640 patients at 15 centers. Nine of the 640 patients were excluded from the data summary of adverse events for the following reasons: 5 patients had their bioprosthesis removed and replaced with another prosthesis during the initial surgery due to difficulty sizing a small aortic root, high mean gradient, or patient prosthesis mismatch; and 4 patients had either a pre-existing or concomitant implant of a mitral valve prosthesis.

The adverse event rates were based on 631 bioprostheses implanted in 631 patients. The cumulative follow-up was 913 patient-years with a mean follow-up of 17 months (SD = 11 months, range = 0 to 42 months).

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Table 2. Observed Adverse Events for the Subcoronary Technique All patients analyzed, N=631, Cumulative follow-up =

913 patient-years

Early Events

Late Events

N % of Patients N % /Patient- Year

All Deaths 31 4.9% 31 3.6%

Bioprostheses-Related or Unexplained 4 0.6% 9 1.0%

Study Bioprosthesis-Related AEs

Thromboembolism

14 2.2% 13 1.5% Permanent Neurological Event 11 1.7% 6 0.7% Transient Neurological Event 3 0.5% 6 0.7%

Bioprosthetic Thrombosis 0 0.0% 1 0.1% Structural Deterioration Nonstructural Dysfunction

0 0.0% 0 0.0%

0 0.0% 0 0.0% Major Antithromboembolic- Related Hemorrhage 10 1.6% 7 0.8% Primary Paravalvular Leak 3 0.5% 8 0.9% Endocarditis 2 0.3% 8 0.9% Primary Hemolysis

0 0.0% 0 0.0% Reoperation 0 0.0% 7 0.8% Explant 0 0.0% 6 0.7%

Actuarial Freedom by Kaplan-Meier (%)

1 Year (95% CI) 3 Years (95% CI)

All Deaths 91.6%

[89.0% - 94.2%]

Bioprostheses-Related or Unexplained 97.9%

[96.5% - 99.3%]

85.9%

[77.5% - 94.3%]

97.5%

[93.5% - 100.0%]

Study Bioprosthesis-Related AEs

Thromboembolism

Permanent Neurological Event 97.3%

Transient Neurological Event 98.5%

Bioprosthetic Thrombosis 99.8%

Structural Deterioration

Nonstructural Dysfunction

Major Antithromboembolic- Related Hemorrhage 97.0%

Primary Paravalvular Leak 98.6%

Endocarditis 98.5%

Primary Hemolysis

Reoperation 98.9%

Explant 99.0%

Hospital or 30 day event for death or 30 day event for adverse events.

Calculations were based on 864 late patient-years.

One late event was a perpherial aterial embolus.

The number of patients remaining at risk at 1 year (N=415) and 3 years (N=57) was used for N in the calculations of the lower confidence limits for the actuarial estimates. The calculation methods are described in the following note.

95.6%

[93.6% - 97.6%]

[95.8% - 98.8%]

[97.3% - 99.7%]

[99.4% - 100.0%]

100.0%

[99.1% - 100.0%]

100.0%

[99.1% - 100.0%]

[95.4% - 98.6%]

[97.5% - 99.7%]

[97.3% - 99.7%]

100.0%

[99.1% - 100.0%]

[97.9% - 99.9%]

[98.0% - 100.0%]

94.6%

[88.8% - 100.0%]

96.6%

[91.9% - 100.0%]

98.2%

[94.7% - 100.0%]

99.8%

[98.6% - 100.0%]

100.0%

[93.7% - 100.0%]

100.0%

[93.7% - 100.0%]

97.0%

[92.6% - 100.0%]

97.6%

[93.6% - 100.0%]

97.9%

[94.2% - 100.0%]

100.0%

[93.7% - 100.0%]

98.6%

[95.6% - 100.0%]

98.7%

[95.8% - 100.0%]

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Notes:

■

AEs = Adverse Events

■

Adverse event rates were calculated as the percentage of patients for early events. For late adverse events, the linearized rates (%/patient-year) were calculated. For time to first event (early or late), actuarial rates using the Kaplan-Meier method and confidence intervals were calculated. For adverse events with no occurrences, the lower two-sided 95% confidence limits for the Kaplan-Meier estimates were calculated as (1-maximum risk), where (1-maximum risk) is equal to (0.025)1/N. If there was no censoring, N would be the total sample size. Since there was censoring, the number of patients remaining at risk at 1 and 3 years was used for N. Using the number of patients remaining at risk ignores the experience of all the patients who were censored before the relevant time points and therefore, overestimates the maximum risk.

29 mm clinical study

A total of 18 Freestyle bioprosthesis, 29 mm, were implanted with the subcoronary technique in 18 patients at 3 centers. Two of the patients were excluded from the data summary of adverse events since they had a Ross procedure performed prior to the 29 mm Freestyle bioprosthesis implant.

One paravalvular leak was reported 65 days postoperatively. No interventions relative to the paravalvular regurgitation have been reported. There were no other bioprosthesis-related adverse events reported. One death was reported: a noncardiac death 342 days postoperatively.

Ten year data

A total of 509 Freestyle bioprosthesis were implanted with the subcoronary technique in 509 patients at 8 centers. The cumulative follow-up was 3206.0 patient-years with a mean follow-up of 6.3 years (SD=3.1 years, range=0 to 11.2 years).

Table 3. Observed Adverse Events for the Subcoronary Technique All patients analyzed, N=509, Cumulative follow-up =

3206.0 patient-years

Early Events Late Events Freedom from Adverse Event (AE) by Kaplan-

N % of

Pts

N %/

Patient-

Year

1 Year

[95% CI]

All Deaths 25 4.9% 206 6.5% 91.7%

[89.3%-94.1%]

Bioprosthesis Related or Unexplained

2 0.4% 41 1.3% 98.3%

[97.2%-99.5%]

Study Bioprosthesis Related AEs

Thromboembolismd,

9 1.8% 77 2.6% 95.2%

[93.3%-97.2%]

Permanent Neurological Event 6 1.2% 35 1.1% 97.9%

[96.6%-99.2%]

Transient Neurological Event

2 0.4% 38 1.3% 97.9%

[96.6%-99.2%]

Bioprosthetic Thrombosis 0 0.0% 2 0.1% 99.6%

[99.0%-100.0%]

Structural Deterioration 0 0.0% 6 0.2% 100.0%

Nonstructural Dysfunction

0 0.0% 1 0.0% 100.0%

Major Antithromboembolic- Related Hemorrhage

8 1.6% 22 0.7% 97.3%

[95.8%-98.8%]

Major Primary Paravalvular Leak 2 0.4% 6 0.2% 99.6%

[99.0%-100.0%]

Endocarditis

1 0.2% 13 0.4% 98.9%

[98.0%-99.9%]

Primary Hemolysis 0 0.0% 0 0.0% 100.0%

Meier (%)

4 Years

[95% CI]

80.9%

[77.4%-84.4%]

96.7%

[94.9%-98.4%]

91.7%

[89.0%-94.4%]

95.1%

[93.0%-97.2%]

96.7%

[95.0%-98.5%]

99.6%

[98.9%-100.0%]

99.8%

[99.3%-100.0%]

100.0%

95.9%

[94.0%-97.9%]

98.7%

[97.5%-99.8%]

98.5%

[97.3%-99.7%]

100.0%

10 Years [95% CI]

44.1%

[35.6%-52.6%]

84.6%

[76.1%-93.2%]

79.7%

[69.8%-89.7%]

88.2%

[80.0%-96.5%]

90.6%

[83.3%-98.0%]

99.6%

[97.9%-100.0%]

97.0%

[92.7%-100.0%]

99.3%

[97.3%-100.0%]

91.3%

[84.1%-98.6%]

98.4%

[95.1%-100.0%]

93.8%

[87.8%-99.9%]

100.0%

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Early Events Late Events Freedom from Adverse Event (AE) by Kaplan-

Meier (%)

N % of

Pts

Reoperation 1 0.2% 21 0.7% 98.9%

Explant 1 0.2% 17 0.5% 99.2%

Freedom from event (early or late) was calculated using the Kaplan-Meier method. Peto's formula was used for the calculation of the standard error of the Kaplan-Meier estimate for the confidence interval for adverse events with at least 1 occurrence.

Early deaths occurred within 30 days of implant if the patient was discharged from the hospital, or at any time after implant if the patient was not discharged from the hospital. Early bioprosthesis-related adverse events occurred within the first 30 days of implant. Early event rates were calculated as the percentage of patients.

Late deaths occurred after 30 days postoperative, if the patient was discharged from the hospital. Late bioprosthesis-related adverse events occurred after 30 days postoperative. Late event rates were calculated as linearized rates (%/patient-year). Calculations for late death rates were based on 3164.7 late patient-years. Calculations for late bioprosthesis-related adverse event rates were based on

3165.7 late patient-years.

Linearized rate for adverse event was based on 2968.9 late patient-years.

One early event was a peripheral arterial embolus, 1 late event was a peripheral arterial embolus and 3 late events were myocardial infarctions.

N %/

Patient-

Year

1 Year

[95% CI]

[98.0%-99.9%]

[98.3%- 100.0%]

4 Years

[95% CI]

98.2%

[96.9%-99.5%]

98.7%

[97.6%- 99.8%]

10 Years [95% CI]

91.7%

[84.8%-98.5%]

92.3%

[85.8%- 98.9%]

5.2. Full-root technique Original clinical study (19 mm, 21 mm, 23 mm, 25 mm, and 27 mm)

A total of 159 Freestyle bioprostheses were implanted with the full-root technique in 159 patients at 14 centers. Two of the 159 patients were excluded from the data summary of adverse events for the following reasons: 2 patients had either a preexisting or concomitant implant of a mitral valve prosthesis.

The adverse event rates were based on 157 bioprostheses implanted in 157 patients. The cumulative follow-up was 189 patient-years with a mean follow-up of 14 months (SD = 13 months, range = 0 to 38 months).

Table 4. Observed Adverse Events for the Full-Root Technique All patients analyzed, N=157, Cumulative follow-up =

189 patient-years

Early Events

Late Events

N % of Patients N % /Patient-

Year

All Deaths 22 14.0% 8 4.5%

Bioprostheses-Related or Unexplained 1 0.6% 4 2.2%

Study Bioprosthesis-Related AEs

Thromboembolism

5 3.2% 6 3.4%

Permanent Neurological Event 2 1.3% 3 1.7%

Transient Neurological Event 2 1.3% 3 1.7% Bioprosthetic Thrombosis Structural Deterioration

Nonstructural Dysfunction

0 0.0% 0 0.0% 0 0.0% 0 0.0%

0 0.0% 0 0.0% Major Antithromboembolic- Related Hemorrhage 2 1.3% 1 0.6% Primary Paravalvular Leak 1 0.6% 0 0.0% Endocarditis

Primary Hemolysis

0 0.0% 0 0.0%

0 0.0% 0 0.0% Reoperation 0 0.0% 0 0.0% Explant 0 0.0% 0 0.0%

Actuarial Freedom by Kaplan-Meier (%)

1 Year (95% CI) 3 Years (95% CI)

All Deaths 79.8%

[72.0% - 87.6%]

Bioprostheses-Related or Unexplained 96.3%

[92.3% - 100.0%]

78.5%

[62.5% - 94.5%]

94.7%

[85.1% - 100.0%]

Study Bioprosthesis-Related AEs

Thromboembolism

Permanent Neurological Event 96.6%

93.3%

[87.9% - 98.7%]

[92.7% - 100.0%]

90.1%

[76.2% - 100.0%]

95.0%

[85.4% - 100.0%]

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Transient Neurological Event 96.3%

[92.2% - 100.0%] Bioprosthetic Thrombosis

100.0%

[95.5% - 100.0%] Structural Deterioration

100.0%

[95.5% - 100.0%] Nonstructural Dysfunction

100.0%

[95.5% - 100.0%] Major Antithromboembolic- Related Hemorrhage 97.7%

[94.4% - 100.0%] Primary Paravalvular Leak 99.2%

[97.3% - 100.0%] Endocarditis

100.0%

[95.5% - 100.0%]

94.7%

[84.3% - 100.0%]

100.0%

[83.2% - 100.0%]

100.0%

[83.2% - 100.0%]

100.0%

[83.2% - 100.0%]

97.7%

[91.0% - 100.0%]

99.2%

[95.3% - 100.0%]

100.0%

[83.2% - 100.0%]

Actuarial Freedom by Kaplan-Meier (%)

1 Year (95% CI) 3 Years (95% CI)

Primary Hemolysis

Reoperation

Explant

Hospital or 30 day event for death or 30 day event for adverse events.

Calculations were based on 179 late patient-years.

One late event was a perpherial aterial embolus.

The number of patients remaining at risk at 1 year (N=81) and 3 years (N=20) was used for N in the calculations of the lower confidence limits for the actuarial estimates. The calculation methods are described in the note following Table 2.

100.0%

[95.5% - 100.0%]

100.0%

[95.5% - 100.0%]

100.0%

[95.5% - 100.0%]

100.0%

[83.2% - 100.0%]

100.0%

[83.2% - 100.0%]

100.0%

[83.2% - 100.0%]

Note: AEs = Adverse Events

29 mm clinical study

A total of 19 Freestyle bioprosthesis, 29 mm, were implanted with the full-root technique in 19 patients at 4 centers. Two of the patients were excluded from the data summary of adverse events for the following reasons: 1 patient had a Ross procedure prior to the 29 mm Freestyle bioprosthesis implant, and 1 patient did not provide informed consent.

A permanent neurological event was reported 13 days postoperatively. The outcome of this event was reported as partially resolved. There were no other bioprosthesis-related adverse events reported.

Ten year data

A total of 178 Freestyle bioprosthesis were implanted with the full-root technique in 178 patients at 8 centers. The cumulative follow-up was 1010.7 patient-years with a mean follow-up of 5.7 years (SD=3.3 years, range=0 to 11.4 years).

Table 5. Observed Adverse Events for the Full-Root Technique All patients analyzed, N=178, Cumulative follow-up =

1010.7 patient-years

Early Events Late Events Freedom from Adverse Event (AE) by Kaplan-

N % of

Pts

N %/

Patient-

Year

1 Year

[95% CI]

All Deaths 16 9.0 53 5.3 87.1%

[82.1%-92.0%]

Bioprosthesis Related or Unexplained

0 0.0 12 1.2 98.1%

[96.0%-100.0%]

Study Bioprosthesis Related AEs

Thromboembolismd,

5 2.8 25 2.6 93.2%

[89.2%-97.1%]

Permanent Neurological Event 3 1.7 9 0.9 96.3%

[93.3%-99.3%]

Meier (%)

4 Years

[95% CI]

77.4%

[70.8%-83.9%]

96.0%

[92.7%-99.4%]

87.6%

[81.9%-93.4%]

94.3%

[90.2%-98.4%]

10 Years [95% CI]

47.3%

[31.4%-63.2%]

88.2%

[74.2%-100.0%]

80.7%

[62.7%-98.6%]

91.1%

[78.2%-100.0%]

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Early Events Late Events Freedom from Adverse Event (AE) by Kaplan-

Meier (%)

N % of

Pts

Transient Neurological Event

2 1.1 14 1.4 96.9%

Bioprosthetic Thrombosis 0 0.0 0 0.0 100.0%

N %/

Patient-

Year

[94.1%-99.6%]

1 Year

[95% CI]

4 Years

[95% CI]

93.3%

[88.8%-97.7%]

100.0%

Structural Deterioration 0 0.0 4 0.4 100.0%

100.0%

Nonstructural Dysfunction

Major Antithromboembolic- Related Hemorrhage

Major Primary Paravalvular Leak 0 0.0 0 0.0 100.0%

0 0.0 1 0.1 100.0%

0 0.0 10 1.0 97.5%

[95.1%-100.0%]

99.2%

[97.6%-100.0%]

96.1%

[92.7%-99.5%]

100.0%

Endocarditis

Primary Hemolysis 0 0.0 0 0.0 100.0%

0 0.0 4 0.4 100.0%

98.0%

[95.6%-100.0%]

100.0%

Reoperation 0 0.0 8 0.8 100.0%

Explant 0 0.0 7 0.7 100.0%

Late deaths occurred after 30 days postoperative, if the patient was discharged from the hospital. Late bioprosthesis-related adverse events occurred after 30 days postoperative. Late event rates were calculated as linearized rates (%/patient-year). Calculations for late death rates were based on 996.4 late patient-years. Calculations for late bioprosthesis-related adverse event rates were based on 997.1 late patient-years.

Linearized rate for adverse event was based on 981.0 late patient-years.

Two late events were peripheral arterial emboli.

97.9%

[95.3%-100.0%]

98.5%

[96.4%-100.0%]

10 Years [95% CI]

89.5%

[75.3%-100.0%]

100.0%

96.0%

[87.1%-100.0%]

99.2%

[95.1%-100.0%]

89.5%

[76.1%-100.0%]

100.0%

97.1%

[89.5%-100.0%]

100.0%

92.3%

[80.5%-100.0%]

93.0%

[81.6%-100.0%]

5.3. Root-inclusion technique Original clinical study (19 mm, 21 mm, 23 mm, 25 mm, and 27 mm)

A total of 83 Freestyle bioprosthesis were implanted with the root-inclusion technique in 83 patients at 14 centers. Three of the 83 patients were excluded from the data summary of adverse events for the following reasons: 3 patients had their bioprosthesis removed and replaced with another prosthesis during the initial surgery due to a leaflet tear during suturing, difficulty seating and orienting the coronaries, or a paravalvular leak.

The adverse event rates were based on 80 bioprostheses implanted in 80 patients. The cumulative follow-up was 139 patientyears with a mean follow-up of 21 months (SD = 13 months, range = 0 to 39 months).

Table 6. Observed Adverse Events for the Root-Inclusion Technique All patients analyzed, N=80, Cumulative follow-up =

139 patient-years

Early Events

Late Events

N % of Patients N % /Patient-

Year

All Deaths 4 5.0% 5 3.8%

Bioprostheses-Related or Unexplained 3 3.8% 3 2.3%

Study Bioprosthesis-Related AEs

Thromboembolism 3 3.8% 7 5.3%

Permanent Neurological Event 0 0.0% 2 1.5%

Transient Neurological Event 3 3.8% 5 3.8% Bioprosthetic Thrombosis Structural Deterioration Nonstructural Dysfunction

0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

Major Antithromboembolic- Related Hemorrhage 2 2.5% 0 0.0%

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Primary Paravalvular Leak 2 2.5% 0 0.0% Endocarditis 1 1.3% 1 0.8% Primary Hemolysis

0 0.0% 0 0.0% Reoperation 2 2.5% 2 1.5% Explant 2 2.5% 2 1.5%

Actuarial Freedom by Kaplan-Meier (%)

1 Year (95% CI) 3 Years (95% CI)

All Deaths 88.8%

[80.9% - 96.7%]

Bioprostheses-Related or Unexplained 91.5%

[84.4% - 98.6%]

87.0%

[72.5% - 100.0%]

91.5%

[79.2% - 100.0%]

Study Bioprosthesis-Related AEs

Thromboembolism 91.3%

[83.8% - 98.8%]

87.2%

[70.2% - 100.0%]

Actuarial Freedom by Kaplan-Meier (%) 1 Year (95% CI) 3 Years (95% CI)

Permanent Neurological Event 98.3%

[95.0% - 100.0%]

Transient Neurological Event 93.0%

[86.1% - 99.9%]

Bioprosthetic Thrombosis

100.0%

[93.5% - 100.0%] Structural Deterioration

100.0%

[93.5% - 100.0%] Nonstructural Dysfunction

100.0%

[93.5% - 100.0%] Major Antithromboembolic- Related Hemorrhage 97.4%

[93.2% - 100.0%] Primary Paravalvular Leak

97.4%

[93.2% - 100.0%] Endocarditis 96.9%

[92.4% - 100.0%] Primary Hemolysis

100.0%

[93.5% - 100.0%] Reoperation 94.4%

[88.5% - 100.0%] Explant 94.4%

[88.5% - 100.0%]

Hospital or 30 day event for death or 30 day event for adverse events.

Calculations were based on 133 late patient-years.

The number of patients remaining at risk at 1 year (N=55) and 3 years (N=18) was used for N in the calculations of the lower confidence limits for the actuarial estimates. The calculation methods are described in the note following Table 2.

96.3%

[87.3% - 100.0%]

87.6%

[71.5% - 100.0%]

100.0%

[81.5% - 100.0%]

100.0%

[81.5% - 100.0%]

100.0%

[81.5% - 100.0%]

97.4%

[90.1% - 100.0%]

97.4%

[90.1% - 100.0%]

96.9%

[89.0% - 100.0%]

100.0%

[81.5% - 100.0%]

94.4%

[84.1% - 100.0%]

94.4%

[84.1% - 100.0%]

Note: AEs = Adverse Events

29 mm clinical study

There were no 29 mm Freestyle bioprosthesis implanted using the root-inclusion technique.

Ten year data

A total of 38 Freestyle bioprosthesis were implanted with the root-inclusion technique in 38 patients at 8 centers. The cumulative follow-up was 270.9 patient-years with a mean follow-up of 7.1 years (SD=3.4 years, range=six days to 11.6 years).

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Table 7. Observed Adverse Events for the Root-Inclusion Technique All patients analyzed, N=38, Cumulative follow-up =

270.9 patient-years

Early Events Late Events Freedom from Adverse Event (AE) by Kaplan-

10 Years

[95% CI]

45.4%

[18.5%-72.2%]

81.5%

[53.4%-100.0%]

N % of

Pts

N %/ Pts-

Year

[95% CI]

1 Year

All Deaths 0 0.0 19 7.1 89.2%

[79.2%-99.2%]

Bioprosthesis Related or Unexplained

0 0.0 6 2.2 91.8%

[82.8%-100.0%]

Meier (%)

4 Years

[95% CI]

83.8%

[71.9%-95.7%]

91.8%

[82.6%-100.0%]

Study Bioprosthesis Related AEs

Thromboembolismd,

Permanent Neurological Event 0 0.0 2 0.8 97.1%

Transient Neurological Event

Bioprosthetic Thrombosis 0 0.0 0 0.0 100.0%

Structural Deterioration

Nonstructural Dysfunction

Major Antithromboembolic- Related Hemorrhage

Major Primary Paravalvular Leak 1 2.6 0 0.0 97.4%

Endocarditis

Primary Hemolysis 0 0.0 0 0.0 100.0%

Reoperation 1 2.6 2 0.8 92.0%

Explant 1 2.6 2 0.8 92.0%

Late deaths occurred after 30 days postoperative, if the patient was discharged from the hospital. Late bioprosthesis-related adverse events occurred after 30 days postoperative. Late event rates were calculated as linearized rates (%/patient-year). Calculations for late death rates were based on 267.9 late patient-years. Calculations for late bioprosthesis-related adverse event rates were based on 267.9 late patient-years.

Linearized rate for adverse event was based on 260.6 late patient-years.

One late event was a myocardial infarction.

Structural deterioration not confirmed with reoperation.

4 10.5 10 3.8 80.7%

[67.1%-94.4%]

[91.5%-100.0%]

4 10.5 7 2.7 83.6%

[70.8%-96.4%]

0 0.0 1 0.4 100.0%

0 0.0 0 0.0 100.0%

1 2.6 2 0.8 97.4%

[92.0%-100.0%]

1 2.6 1 0.4 94.4%

[86.8%-100.0%]

[83.0%-100.0%]

77.6%

[62.9%-92.3%]

97.1%

[91.3%-100.0%]

80.5%

[66.6%-94.4%]

100.0%

97.4%

[91.8%-100.0%]

97.4%

[91.8%-100.0%]

94.4%

[86.6%-100.0%]

100.0%

92.0%

[82.8%-100.0%]

92.0%

[82.8%-100.0%]

68.1%

[24.5%-100.0%]

93.4%

[72.4%-100.0%]

80.5%

[45.7%-100.0%]

100.0%

90.9%

[69.0%-100.0%]

100.0%

90.8%

[68.7%-100.0%]

97.4%

[84.7%-100.0%]

94.4%

[76.6%-100.0%]

100.0%

92.0%

[71.1%-100.0%]

92.0%

[71.1%-100.0%]

5.4. Potential adverse events

Adverse events potentially associated with the use of bioprosthetic heart valves include:

■

Cardiac dysrhythmias

■

Death

■

Endocarditis

■

Hemolysis

■

Hemorrhage, anticoagulant/antiplatelet-related

■

Leak, transvalvular or paravalvular

■

Nonstructural dysfunction (pannus, suture, inappropriate sizing, or other)

■

Structural deterioration (calcification, leaflet tear, intracuspal hematoma, pseudoaneurysm, or other)

■

Thromboembolism

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■

1000

800

600

400

200

0 1 2 3 4

Total

Subcoronary

Full root

Root inclusion

Follow-up (years)

Number of patients

Valve thrombosis

■

Root dilatation

■

Angina

■

Infection, other than endocarditis

■

Heart failure

■

Hemolytic anemia

■

Myocardial infarction

■

Acute kidney injury

■

Renal failure

It is possible that these complications could lead to the following:

■

reoperation

■

explantation

■

permanent disability

■

death

6. Clinical Studies

6.1. Original clinical study (19 mm, 21 mm, 23 mm, 25 mm, and 27 mm)

A prospective non-randomized multicenter international study evaluated the Freestyle bioprosthesis with patient follow-up out to 3 years. A total of 882 patients received the bioprosthesis. Patients were evaluated preoperatively, within 30 days postoperatively, at 3 to 6 months, and annually. The cumulative follow-up was 1246 patient-years with a mean follow-up of 17 months (SD = 12 months, range = 0 to 42 months).

The following graph shows the number of patients implanted by technique versus duration of follow-up and the subsequent table shows the breakdown of duration of follow-up by technique and by valve size.

Figure 7. Number of patients by duration of follow-up and implant technique: all patients implanted, approved sizes, N=882

Duration of follow-up (years)

Implant Technique 0 1 2 3 3.5

Number of patients by technique by year

Total 882 552 348 96 1 Subcoronary 640 416 255 58 1 Full-Root 159 81 48 20 0 Root- Inclusion 83 55 45 18 0

Size Number of patients by size by year 19 mm 36 22 12 4 0 21 mm 149 91 57 13 0 23 mm 250 156 99 26 1 25 mm 236 153 99 31 0 27 mm 212 130 81 22 0

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Table 8. Patient Characteristics: Subcoronary Technique All patients analyzed, N=631

Age at implant in years (mean ± SD, N [min., max.]) 71±8, 631 [32, 91]

Gender (% male /% female) 53% /47% Etiology

Stenosis—percent of patients with stenosis alone [% (num-

43% (272/631)

ber in subgroup/N)] Insufficiency—percent of patients with insufficiency alone [%

6% (39/631)

(number in subgroup/N)] Mixed—percent of patients with stenosis and insufficiency [%

50% (318/631)

(number in subgroup/N)] Othera—percent of patients with etiology other than stenosis

0% (2/631)

and insufficiency [% (number in subgroup/N)]

One patient had incidental replacement of a previously implanted prothesis and 1 patient had endocaditis without lesion.

Table 9. Patient Characteristics: Full-Root Technique All patients analyzed, N=157

Age at implant in years (mean ± SD, N [min., max.]) 70±8, 157 [38, 87]

Gender (% male /% female) 51% /49% Etiology

Stenosis—percent of patients with stenosis alone [% (num-

31% (49/157)

ber in subgroup/N)] Insufficiency—percent of patients with insufficiency alone [%

21% (33/157)

(number in subgroup/N)] Mixed—percent of patients with stenosis and insufficiency [%

47% (74/157)

(number in subgroup/N)] Othera—percent of patients with etiology other than stenosis

1% (1/157)

and insufficiency [% (number in subgroup/N)]

One patient had a dissecting ascending aortic aneurysm.

Table 10. Patient Characteristics: Root Inclusion Technique All patients analyzed, N=80

Age at implant in years (mean ± SD, N [min., max.]) 69±9, 80 [40, 90]

Gender (% male /% female) 73% /28% Etiology

Stenosis—percent of patients with stenosis alone [% (num-

41% (33/80)

ber in subgroup/N)] Insufficiency—percent of patients with insufficiency alone [%

11% (9/80)

(number in subgroup/N)] Mixed—percent of patients with stenosis and insufficiency [%

48% (38/80)

(number in subgroup/N)]

Table 11. Effectiveness Outcomes, Functional NYHA: Subcoronary Technique All patients analyzed: N=631, mean ± SD

(number), percent (numerator/N)

Endpoint Preoperative 3-6 Months 1 Year Functional NYHA 2.9 ± 0.6 (631) 1.2 ± 0.5 (525) 1.2 ± 0.5 (454)

I - % of pts. in NYHA class I 2% (14/631) 80% (419/525) 84% (380/454) II - % of pts. in NYHA class II 20% (129/631) 18% (96/525) 14% (64/454) III - % of pts. in NYHA class III 63% (400/631) 2% (10/525) 2% (8/454) IV - % of pts. in NYHA class IV 14% (88/631) 0% (0/525) 0% (2/454)

Table 12. Effectiveness Outcomes, Functional NYHA: Full-Root Technique All patients analyzed: N=157, mean ± SD (number),

percent (numerator/N)

Endpoint Preoperative 3-6 Months 1 Year Functional NYHA 2.9 ± 0.7 (155) 1.1 ± 0.2 (114) 1.1 ± 0.3 (87)

I - % of pts. in NYHA class I 1% (2/155) 94% (107/114) 91% (79/87) II - % of pts. in NYHA class II 20% (31/155) 6% (7/114) 9% (8/87) III - % of pts. in NYHA class III 61% (95/155) 0% (0/114) 0% (0/87) IV - % of pts. in NYHA class IV 17% (27/155) 0% (0/114) 0% (0/87)

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Table 13. Effectiveness Outcomes, Functional NYHA: Root-Inclusion Technique All patients analyzed: N=80, mean ± SD

(number), percent (numerator/N)

Endpoint Preoperative 3-6 Months 1 Year Functional NYHA 2.7 ± 0.6 (80) 1.2 ± 0.5 (60) 1.1 ± 0.3 (54)

I - % of pts. in NYHA class I 5% (4/80) 87% (52/60) 91% (49/54) II - % of pts. in NYHA class II 26% (21/80) 10% (6/60) 9% (5/54) III - % of pts. in NYHA class III 68% (54/80) 3% (2/60) 0% (0/54) IV - % of pts. in NYHA class IV 1% (1/80) 0% (0/60) 0% (0/54)

Table 14. Effectiveness Outcomes, Hemodynamics, Valvular Regurgitation: Subcoronary Technique All patients analyzed:

N=631, mean ± SD (number), percent (numerator/N)

Endpoint <30 Days 3-6 Months 1 Year Valvular Regurgitation

0.3 ± 0.4 (552) 0.3 ± 0.5 (523) 0.3 ± 0.4 (456) 0 % of pts. with no Rg. 65% (358/552) 62% (326/523) 65% (296/456) <1+ % of pts. with <mild Rg. 15% (82/552) 17% (87/523) 20% (92/456) 1+ % of pts. with mild Rg. 20% (108/552) 19% (101/523) 13% (61/456) 2+ % of pts. with mod Rg. 1% (3/552) 2% (8/523) 1% (5/456) 3+/4+ % of pts. with mod/severe

0% (1/552) 0% (1/523) 0% (2/456)

Rg.

The data reflect regurgitation noted at all locations combined. Data coded as “trivial/mild” were included in the category “<1+, <mild regurgitation.” Data in the category “<1+” were coded as “0.5” for the calculation of mean ± SD.

Note: Rg = Regurgitation

Table 15. Effectiveness Outcomes, Hemodynamics, Valvular Regurgitation: Full-Root Technique All patients analyzed: N=157,

mean ± SD (number), percent (numerator/N)

Endpoint <30 Days 3-6 Months 1 Year Valvular Regurgitation

0.1 ± 0.3 (131) 0.1 ± 0.3 (113) 0.1 ± 0.2 (90) 0 % of pts. with no Rg. 86% (113/131) 87% (98/113) 87% (78/90) <1+ % of pts. with <mild Rg. 8% (10/131) 8% (9/113) 11% (10/90) 1+ % of pts. with mild Rg. 5% (7/131) 4% (5/113) 2% (2/90) 2+ % of pts. with mod Rg. 1% (1/131) 1% (1/113) 0% (0/90) 3+/4+ % of pts. with mod/severe

0% (0/131) 0% (0/113) 0% (0/90)

Rg.

Note: Rg = Regurgitation

Table 16. Effectiveness Outcomes, Hemodynamics, Valvular Regurgitation: Root-Inclusion Technique All patients analyzed:

N=80, mean ± SD (number), percent (numerator/N)

Endpoint <30 Days 3-6 Months 1 Year Valvular Regurgitation

0.2 ± 0.4 (75) 0.1 ± 0.3 (63) 0.2 ± 0.3 (51) 0 % of pts. with no Rg. 77% (58/75) 79% (50/63) 76% (39/51) <1+ % of pts. with <mild Rg. 15% (11/75) 14% (9/63) 16% (8/51) 1+ % of pts. with mild Rg. 5% (4/75) 6% (4/63) 8% (4/51) 2+ % of pts. with mod Rg. 3% (2/75) 0% (0/63) 0% (0/51) 3+/4+ % of pts. with mod/severe

0% (0/75) 0% (0/63) 0% (0/51)

Rg.

Note: Rg = Regurgitation

Table 17. Effectiveness Outcomes, Hemodynamics, Mean Pressure Gradient: Subcoronary Technique All patients analyzed:

N=631, number in subgroup/N, mean ± SD [min., max.]

Endpoint <30 Days 3-6 Months 1 Year Mean Pressure Gradient (mm Hg)

19 mm 19/27, 17.6 ± 7.6

[8.0, 42.0]

21 mm 100/117, 14.6 ± 8.1

[1.0, 48.0]

19/27, 12.0 ± 5.7

[2.0, 23.0]

91/117, 9.0 ± 6.2

[1.0, 47.0]

18/27, 11.7 ± 4.7

[5.0, 19.0]

83/117, 9.8 ± 7.4

[0.8, 51.0]

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Endpoint <30 Days 3-6 Months 1 Year

23 mm 165/191, 12.9 ± 6.9

[2.0, 39.0]

25 mm 145/167, 9.1 ± 4.6

[1.0, 28.0]

27 mm 112/129, 7.3 ± 4.1

[1.0, 22.0]

Table 18. Effectiveness Outcomes, Hemodynamics, Mean Pressure Gradient: Full-Root Technique All patients analyzed:

N=157, number in subgroup/N, mean ± SD [min., max.]

Endpoint <30 Days 3-6 Months 1 Year Mean Pressure Gradient (mm Hg)

19 mm 7/7, 11.9 ± 6.0

[6.0, 23.0]

21 mm 14/21, 7.8 ± 3.4

[2.0, 14.0]

23 mm 20/32, 6.8 ± 3.8

[0.9, 13.0]

25 mm 31/35, 4.9 ± 2.9

[1.0, 12.0]

27 mm 59/62, 4.4 ± 3.4

[1.0, 20.0]

Table 19. Effectiveness Outcomes, Hemodynamics, Mean Pressure Gradient: Root-Inclusion Technique All patients analyzed:

N=80, number in subgroup/N, mean ± SD [min., max.]

156/191, 8.9 ± 5.9

[1.0, 35.0]

146/167, 5.5 ± 3.3

[1.0, 19.0]

110/129, 5.0 ± 3.7

[1.0, 30.0]

7/7, 13.4 ± 6.7

[7.0, 27.0]

12/21, 7.6 ± 3.5

[2.0, 14.0]

20/32, 5.4 ± 3.4

[1.0, 12.0]

29/35, 4.2 ± 2.9

[1.0, 12.0]

46/62, 3.8 ± 2.9

[0.7, 15.0]

138/191, 8.8 ± 6.8

[0.0, 57.0]

119/167, 5.1 ± 3.3

[0.0, 18.0]

92/129, 4.4 ± 2.9

[0.7, 13.0]

5/7, 16.8 ± 7.4

[9.0, 27.1]

9/21, 7.2 ± 4.0

[3.0, 14.0]

13/32, 7.1 ± 3.7

[1.6, 14.0]

23/35, 4.5 ± 3.4

[1.0, 17.0]

38/62, 3.2 ± 1.8

[1.0, 8.0]

Endpoint <30 Days 3-6 Months 1 Year Mean Pressure Gradient (mm Hg)

21 mm 4/5, 12.3 ± 7.0

[3.0, 20.0]

23 mm 21/25, 13.8 ± 10.7

[2.0, 52.0]

25 mm 29/30, 9.6 ± 6.7

[2.0, 28.0]

27 mm 19/20, 6.4 ± 3.4

[2.0, 14.0]

The expected orifice area indexed to body surface area in an adult should be greater than or equal to 1.5 cm2/m2. The following effective orifice area data are not indexed to body surface area.

Table 20. Effectiveness Outcomes, Hemodynamics, Effective Orifice Area: Subcoronary Technique All patients analyzed:

N=631, number in subgroup/N, mean ± SD [min., max.]

Endpoint <30 Days 3-6 Months 1 Year Effective Orifice Area (cm2)

19 mm 19/27, 0.9 ± 0.2

[0.5, 1.4]

21 mm 97/117, 1.3 ± 0.4

[0.5, 2.4]

23 mm 160/191, 1.4 ± 0.5

[0.5, 3.7]

25 mm 143/167, 1.8 ± 0.6

[0.4, 3.9]

27 mm 110/129, 2.2 ± 0.7

[0.8, 5.1]

91/117, 1.5 ± 0.5

154/191, 1.7 ± 0.5

146/167, 2.0 ± 0.5

109/129, 2.4 ± 0.6

3/5, 8.0 ± 2.6

[6.0, 11.0]

17/25, 10.3 ± 12.1

[2.0, 54.0]

25/30, 8.2 ± 6.7

[2.0, 29.0]

18/20, 4.4 ± 2.4

[1.0, 8.0]

19/27, 1.1 ± 0.3

[0.6, 1.7]

[0.8, 4.3]

[0.6, 3.6]

[0.9, 3.5]

[1.2, 4.1]

2/5, 9.0 ± 1.4

[8.0, 10.0]

14/25, 8.7 ± 8.8

[2.0, 36.0]

17/30, 7.6 ± 6.8

[2.0, 29.0]

15/20, 3.7 ± 2.2

[1.0, 8.0]

18/27, 1.1 ± 0.3

[0.7, 1.7]

82/117, 1.4 ± 0.4

[0.4, 3.1]

137/191, 1.7 ± 0.5

[0.8, 3.9]

119/167, 2.0 ± 0.5

[0.8, 3.5]

92/129, 2.5 ± 0.7

[1.3, 4.4]

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Table 21. Effectiveness Outcomes, Hemodynamics, Effective Orifice Area: Full-Root Technique All patients analyzed: N=157,

number in subgroup/N, mean ± SD [min., max.]

Endpoint <30 Days 3-6 Months 1 Year Effective Orifice Area (cm2)

19 mm 7/7, 1.3 ± 0.4

[0.5, 1.7]

21 mm 14/21, 1.5 ± 0.6

[0.9, 3.3]

23 mm 19/32, 1.7 ± 0.4

[0.7, 2.4]

25 mm 31/35, 2.1 ± 0.6

[1.1, 3.8]

27 mm 59/62, 2.1 ± 0.6

[1.1, 4.0]

Table 22. Effectiveness Outcomes, Hemodynamics, Effective Orifice Area: Root-Inclusion Technique All patients analyzed:

N=80, number in subgroup/N, mean ± SD [min., max.]

Endpoint <30 Days 3-6 Months 1 Year Effective Orifice Area (cm2)

21 mm 4/5, 1.6 ± 0.8

[1.0, 2.8]

23 mm 21/25, 1.6 ± 0.6

[0.8, 3.0]

25 mm 29/30, 1.9 ± 0.8

[0.9, 3.4]

27 mm 19/20, 2.4 ± 0.7

[1.4, 4.0]

7/7, 1.1 ± 0.3

[0.6, 1.5]

12/21, 1.7 ± 0.4

[1.2, 2.3]

19/32, 1.8 ± 0.5

[1.2, 3.0]

29/35, 2.1 ± 0.5

[1.1, 3.8]

46/62, 2.3 ± 0.5

[1.3, 3.3]

2/5, 1.4 ± 0.2

[1.3, 1.5]

16/25, 1.8 ± 0.5

[0.9, 3.0]

22/30, 2.2 ± 0.8

[1.2, 3.8]

18/20, 2.7 ± 0.7

[1.8, 4.7]

5/7, 1.0 ± 0.1

[0.9, 1.1]

9/21, 1.4 ± 0.3

[1.1, 1.9]

13/32, 2.0 ± 0.5

[1.5, 3.3]

24/35, 2.2 ± 0.6

[1.3, 3.5]

37/62, 2.4 ± 0.7

[1.3, 4.3]

2/5, 1.0 ± 0.1

[0.9, 1.2]

14/25, 1.9 ± 0.4

[1.1, 3.1]

17/30, 2.2 ± 0.8

[1.0, 3.6]

15/20, 3.0 ± 0.9

[1.7, 5.0]

6.2. 29 mm clinical study

A prospective non-randomized multicenter study evaluated the Freestyle bioprosthesis, 29 mm, with patient follow-up out to 1 year. A total of 37 patients received the 29 mm bioprosthesis. Patients were evaluated preoperatively, within 30 days postoperatively, at 3 to 6 months, and annually. The cumulative follow-up was 21 patient-years with a mean follow-up of 8 months (SD = 6 months, range = 0 to 24 months).

Note: the total number of patients in this study data will reference 33 patients. (Four out of 37 patients did not meet study requirements.)

Table 23. Patient Characteristics: All patients analyzed: N=33

Age at implant in years (mean ± SD, N [min., max.]) 61±12, 33 [34, 90] Gender (% male /% female) 100% /0% Etiology

Stenosis—percent of patients with stenosis alone [% (number in subgroup/N)]

Insufficiency—percent of patients with insufficiency alone [% (number in subgroup/N)]

Mixed—percent of patients with stenosis and insufficiency [% (number in subgroup/N)]

Table 24. Effectiveness Outcomes, Functional NYHA: All patients analyzed: N=33 percent (numerator/N)

Endpoint Preoperative 3-6 Months 1 Year Functional NYHA

I - % of pts. in NYHA class I 9% (3/32) 89% (24/27) 100% (15/15) II - % of pts. in NYHA class II 34% (11/32) 11% (3/27) 0% (0/15) III - % of pts. in NYHA class III 47% (15/32) 0% (0/27) 0% (0/15) IV - % of pts. in NYHA class IV 9% (3/32) 0% (0/27) 0% (0/15)

Note: With smaller sample sizes, only percent and numerator/N are provided. One patient was unable to have NYHA assessed because of emergent surgery.

12% (4/33)

36% (12/33)

52% (17/33)

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Table 25. Effectiveness Outcomes, Hemodynamics, Valvular Regurgitation: All patients analyzed: N=33, percent (numerator/N)

Endpoint <30 Days 3-6 Months 1 Year Valvular Regurgitation

0 % of pts. with no Rg. 72% (21/29) 80% (20/25) 57% (8/14) <1+ % of pts. with <mild Rg. 21% (6/29) 8% (2/25) 21% (3/14) 1+ % of pts. with mild Rg. 3% (1/29) 8% (2/25) 14% (2/14) 2+ % of pts. with mod Rg. 3% (1/29) 4% (1/25) 7% (1/14) 3+/4+ % of pts. with mod/severe Rg. 0% (0/29) 0% (0/25) 0% (0/14)

The data reflect regurgitation noted at all locations.

Note: With smaller sample sizes, only percent and numerator/N are provided Note: Rg = Regurgitation

Table 26. Effectiveness Outcomes, Hemodynamics, Mean Pressure Gradient and Effective Orifice Area: All patients analyzed:

N=33, number in subgroup/N, mean ± SD [min., max.]

Endpoint <30 Days 3-6 Months 1 Year

Mean Pressure Gradient 29/33, 7.9 ± 5.0 21/33, 6.5 ± 3.4 13/33, 5.5 ± 4.3

(mm Hg) [3.0, 19.0] [2.0, 17.0] [3.0, 19.0]

Effective Orifice Area 23/33, 2.2 ± 0.8 18/33, 2.3 ± 0.6 13/33, 2.5 ± 0.6

(cm2)

[0.9, 4.3] [1.1, 3.4] [1.7, 3.7]

6.3. Ten year data

A prospective, multi-center, non-randomized, clinical study evaluated the long-term safety and effectiveness of the Freestyle bioprosthesis. A total of 725 patients received the bioprosthesis. Patients were evaluated preoperatively, within 30 days of implant, at 3 to 6 months postoperative, at 1 year postoperative, and annually thereafter. The cumulative follow-up was

4487.6 patient-years with a mean follow-up of 6.2 years (SD=3.2 years, range 0 to 11.6 years). Table 27. Patient Characteristics: Subcoronary Technique All patients analyzed: N = 509

Age at implant in years (mean ± SD, N [min., max.]) 72 ± 7, 509 [36, 91] Gender (% male /% female) 53% / 47% Etiology

Stenosis—% of pts. with stenosis alone (% (number in sub-

44% (222/509)

group/N)) Insufficiency—% of pts. with insufficiency alone (% (number

6% (33/509)

in subgroup/N)) Mixed—% of pts. with stenosis and insufficiency (% (number

50% (253/509)

in subgroup/N)) Othera - % of pts. with etiology other than stenosis or insuffi-

0% (1/509)

ciency (% (number in subgroup/N))

One patient had incidental replacement of a previously implanted prosthesis.

Table 28. Patient Characteristics: Full-Root Technique All patients analyzed: N=178

Age at implant in years (mean ± SD, N [min., max.]) 70 ± 8, 178 [41, 87] Gender (% male /% female) 58% / 42% Etiology

Stenosis—% of pts. with stenosis alone (% (number in sub-

38% (68/177)

group/N)) Insufficiency—% of pts. with insufficiency alone (% (number

18% (32/177)

in subgroup/N)) Mixed—% of pts. with stenosis and insufficiency (% (number

43% (76/177)

in subgroup/N)) Othera - % of pts. with etiology other than stenosis or insuffi-

1% (1/177)

ciency (% (number in subgroup/N))

One patient had a dissecting ascending aortic aneurysm and 1 patient did not have the etiology indicated.

Table 29. Patient Characteristics: Root-Inclusion Technique All patients analyzed: N = 38

Age at implant in years (mean ± SD, N [min., max.]) 69 ± 10, 38 [40, 90] Gender (% male /% female) 71% / 29% Etiology

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Stenosis—% of pts. with stenosis alone [% (number in sub-

58% (22/38)

group/N)] Insufficiency—% of pts. with insufficiency alone [% (number

5% (2/38)

in subgroup/N)] Mixed—% of pts. with stenosis and insufficiency [% (number

37% (14/38)

in subgroup/N)]

Table 30. Effectiveness Outcomes, Functional NYHA: Subcoronary Technique All patients analyzed: N = 509, percent

(numerator/N)

Endpoint Preoperative

1 Year 4 Years 8 Years 10 Years

Functional NYHA

I - % of pts. in NYHA class I

II - % of pts. in NYHA class II

III- % of pts. in NYHA class III

IV-% of pts. in NYHA class IV

One patient did not have NYHA indicated.

(17/508)

27%

(137/508)

59%

(299/508)

11%

(55/508)

86%

(372/432)

12%

(53/432)

(5/432)

(2/432)

73%

(240/327)

22%

(71/327)

(14/327)

(2/327)

65%

(110/170)

27%

(46/170)

(12/170)

(2/170)

Table 31. Effectiveness Outcomes, Functional NYHA: Full-Root Technique All patients analyzed: N = 178, percent

(numerator/N)

Endpoint Preoperative

1 Year 4 Years 8 Years 10 Years

Functional NYHA

I - % of pts. in NYHA class I

II - % of pts. in NYHA class II

III- % of pts. in NYHA class III

IV-% of pts. in NYHA class IV

Three patients were unable to have NYHA assessed.

(1/175)

21%

(36/175)

65%

(114/175)

14%

(24/175)

95%

(143/150)

(7/150)

(0/150)

91%

(105/115)

(8/115)

(2/115)

(0/115)

85%

(40/47)

13%

(6/47)

(1/47)

(0/47)

Table 32. Effectiveness Outcomes, Functional NYHA: Root-Inclusion Technique All patients analyzed: N = 38, percent

(numerator/N)

68%

(44/65)

23%

(15/65)

(6/65)

(0/65)

69%

(11/16)

25%

(4/16)

(1/16)

(0/16)

Endpoint Preoperative 1 Year 4 Years 8 Years 10 Years Functional NYHA

I - % of pts. in NYHA class I

II - % of pts. in NYHA class II

III- % of pts. in NYHA class III

IV-% of pts. in NYHA class IV

(1/38)

11%

(4/38)

87%

(33/38)

(0/38)

100%

(33/33)

(0/33)

93%

(26/28)

(2/28)

(0/28)

81%

(13/16)

(1/16)

13%

(2/16)

(0/16)

83%

(10/12)

(0/12)

17%

(2/12)

(0/12)

Table 33. Effectiveness Outcomes, Hemodynamics, Valvular Regurgitation: Subcoronary Technique All patients analyzed: N =

509, percent (numerator/N)

Endpoint 1 Year 4 Years 8 Years 10 Years Valvular Regurgitation

0 % of pts. with no Rg. 60%

<1+ % of pts. with <mild Rg. 20%

(253/425)

(86/425)

54%

(155/287)

27%

(78/287)

59%

(89/152)

26%

(40/152)

51%

(26/51)

25%

(13/51)

Instructions for Use English 19

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Endpoint 1 Year 4 Years 8 Years 10 Years

1+ % of pts. with mild Rg. 18%

(78/425)

2+ % of pts. with mod Rg. 2%

(8/425)

3+/4+ % of pts. with mod severe/severe Rg.

The data reflect regurgitation (Rg) noted at all locations combined. Data coded as “trivial/mild” were included in the category “<1+, <mild Rg.”.

(0/425)

16%

(45/287)

(9/287)

(0/287)

13%

(20/152)

(3/152)

(0/152)

18%

(9/51)

(2/51)

(1/51)

Table 34. Effectiveness Outcomes, Hemodynamics, Valvular Regurgitation: Full-Root Technique All patients analyzed: N=178,

percent (numerator/N)

Endpoint 1 Year 4 Years 8 Years 10 Years Valvular Regurgitation

0 % of pts. with no Rg. 90%

<1+ % of pts. with <mild Rg. 8%

1+ % of pts. with mild Rg. 2%

2+ % of pts. with mod Rg. 0%

3+/4+ % of pts. with mod severe/ severe Rg.

The data reflect regurgitation (Rg) noted at all locations combined. Data coded as “trivial/mild” were included in the category “<1+, <mild Rg.”.

(136/151)

(12/151)

(3/151)

(0/151)

90%

(100/111)

(5/111)

(1/111)

(0/111)

87%

(34/39)

(2/39)

(1/39)

(0/39)

79%

(11/14)

(1/14)

(0/14)

Table 35. Effectiveness Outcomes, Hemodynamics, Valvular Regurgitation: Root-Inclusion Technique All patients analyzed:

N=38, percent (numerator/N)

Endpoint 1 Year 4 Years 8 Years 10 Years Valvular Regurgitation

0 % of pts. with no Rg. 78% (25/32) 83% (25/30) 71% (10/14) 50% (4/8) <1+ % of pts. with <mild Rg. 13% (4/32) 10% (3/30) 21% (3/14) 38% (3/8) 1+ % of pts. with mild Rg. 6% (2/32) 7% (2/30) 0% (0/14) 13% (1/8) 2+ % of pts. with mod Rg. 3% (1/32) 0% (0/30) 7% (1/14) 0% (0/8) 3+/4+ % of pts. with mod

0% (0/32) 0% (0/30) 0% (0/14) 0% (0/8)

severe/severe Rg.

The data reflect regurgitation (Rg) noted at all locations combined. Data coded as “trivial/mild” were included in the category “<1+, <mild Rg.”.

Table 36. Effectiveness Outcomes, Hemodynamics, Mean Pressure Gradient: Subcoronary Technique All patients analyzed:

N=509, number in subgroup/N, mean ± SD [min., max.]

Endpoint 1 Year 4 Years 8 Years 10 Years Mean Pressure Gradient

(mm Hg)

19 mm 23/31, 12.7 ± 5.7

[5.0, 30.0]

21 mm 74/103, 11.1 ± 6.8

[2.0, 29.0]

23 mm 117/133, 9.5 ± 4.9

[1.0, 26.3]

25 mm 112/137, 6.3 ± 3.8

[0.0, 19.0]

27 mm 86/96, 5.7 ± 3.8

[0.7, 19.0]

29 mm 7/9, 5.9 ± 3.8

[3.0, 14.0]

14/31, 12.5 ± 7.2

[4.0, 28.0]

47/103, 9.7 ± 4.9

[1.7, 24.0]

75/133, 9.7 ± 5.7

[0.8, 28.0]

77/137, 6.3 ± 4.4

[0.0, 24.0]

59/96, 5.7 ± 4.3

[1.0, 20.0]

4/9, 6.3 ± 2.9

[3.3, 10.3]

4/31, 14.9 ± 5.1

[7.9, 19.2]

25/103, 12.8 ± 7.8

[4.0, 29.0]

34/133, 9.3 ± 4.4

[2.8, 22.1]

39/137, 6.7 ± 4.4

[1.0, 22.0]

38/96, 5.2 ± 3.7

[0.8, 14.8]

0/9, --

[--]

0/31, --

[--]

7/103, 13.9 ± 9.2

[4.3, 33.0]

10/133, 9.9 ± 5.1

[4.3, 19.8]

17/137, 7.6 ± 9.2

[2.0, 40.4]

10/96, 6.3 ± 5.4

[2.4, 17.9]

0/9, --

[--]

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Table 37. Effectiveness Outcomes, Hemodynamics, Mean Pressure Gradient: Full-Root Technique All patients analyzed:

N=178, number in subgroup/N, mean ± SD [min., max.]

Endpoint 1 Year 4 Years 8 Years 10 Years Mean Pressure Gradient

(mm Hg)

19 mm 7/8, 12.0 ± 5.2

[6.0, 21.0]

21 mm 16/22, 7.6 ± 4.3

[2.0, 15.0]

23 mm 25/33, 6.9 ± 3.4

[0.9, 14.0]

25 mm 32/35, 4.8 ± 2.8

[2.0, 17.0]

27 mm 55/64, 3.5 ± 1.9

[1.0, 8.0]

29 mm 11/16, 3.7 ± 1.5

[1.6, 6.0]

Table 38. Effectiveness Outcomes, Hemodynamics, Mean Pressure Gradient: Root-Inclusion Technique All patients analyzed:

N=38, number in subgroup/N, mean ± SD [min., max.]

Endpoint 1 Year 4 Years 8 Years 10 Years Mean Pressure Gradient

(mm Hg)

19 mm -- -- -- -21 mm 3/4, 10.3 ± 5.5

[5.0, 16.0]

23 mm 9/11, 5.7 ± 3.8

[2.0, 15.0]

25 mm 9/13, 6.4 ± 4.1

[3.0, 14.0]

27 mm 8/10, 3.8 ± 2.2

[1.0, 8.0]

29 mm -- -- -- --

Table 39. Effectiveness Outcomes, Hemodynamics, Effective Orifice Area: Subcoronary Technique All patients analyzed:

N=509, number in subgroup/N, mean ± SD [min., max.]

5/8, 11.6 ± 3.8

[7.0, 16.0]

12/22, 7.4 ± 3.9

[3.0, 16.0]

18/33, 7.3 ± 3.2

[2.0, 17.0]

26/35, 4.7 ± 2.6

[1.1, 11.0]

42/64, 4.2 ± 2.7

[0.8, 13.0]

1/16, 3.1 ± --

[3.1, 3.1]

2/4, 8.0 ± 2.8

[6.0, 10.0]

9/11, 4.4 ± 2.8

[2.0, 9.0]

10/13, 6.1 ± 3.5

[2.0, 15.0]

8/10, 4.0 ± 1.5

[1.1, 5.5]

3/8, 7.5 ± 0.5

[7.0, 8.0]

4/22, 10.8 ± 9.3

[4.0, 24.2]

6/33, 6.7 ± 3.9

[2.3, 13.2]

11/35, 4.4 ± 2.1

[2.0, 7.9]

14/64, 4.8 ± 3.3

[0.6, 10.0]

0/16, --

[--]

1/4, 1.5 ± --

[1.5, 1.5]

4/11, 5.1 ± 2.9

[1.5, 7.7]

5/13, 6.2 ± 6.6

[2.4, 18.0]

4/10, 5.9 ± 1.9

[3.6, 8.3]

1/8, 7.2 ± --

[7.2, 7.2]

1/22, 17.6 ± --

[17.6, 17.6]

2/33, 7.6 ± 1.5

[6.5, 8.7]

5/35, 5.2 ± 1.9

[3.5, 8.1]

5/64, 6.5 ± 4.2

[1.1, 11.7]

0/16, --

[--]

0/4, --

[--]

2/11, 6.4 ± 3.6

[3.9, 9.0]

2/13, 6.6 ± 5.4

[2.8, 10.5]

4/10, 13.4 ± 15.5

[3.9, 36.5]

Endpoint 1 Year 4 Years 8 Years 10 Years Effective Orifice Area

(cm2)

19 mm 23/31, 1.1 ± 0.3

[0.7, 1.7]

21 mm 73/103, 1.4 ± 0.3

[0.6, 2.2]

23 mm 117/133, 1.6 ± 0.4

[0.8, 2.7]

25 mm 112/137, 2.0 ± 0.5

[1.0, 3.9]

27 mm 85/96, 2.4 ± 0.5

[1.3, 4.2]

29 mm 7/9, 2.7 ± 0.9

[1.9, 4.4]

15/31, 1.1 ± 0.3

[0.6, 1.7]

47/103, 1.3 ± 0.4

[0.4, 2.3]

75/133, 1.5 ± 0.4

[0.6, 3.0]

79/137, 2.0 ± 0.4

[0.9, 3.4]

59/96, 2.3 ± 0.5

[1.1, 3.3]

4/9, 2.1 ± 0.3

[1.8, 2.4]

4/31, 1.0 ± 0.2

[0.7, 1.2]

23/103, 1.3 ± 0.4

[0.6, 2.6]

33/133, 1.5 ± 0.4

[0.9, 2.6]

38/137, 1.8 ± 0.4

[1.1, 2.8]

36/96, 2.2 ± 0.6

[1.0, 3.7]

0/9, --

[--]

Instructions for Use English 21

0/31, --

[--]

7/103, 1.1 ± 0.4

[0.5, 1.8]

10/133, 1.4 ± 0.5

[0.8, 2.0]

18/137, 1.7 ± 0.4

[0.7, 2.3]

11/96, 1.8 ± 0.4

[1.2, 2.4]

0/9, --

[--]

Page 24

Table 40. Effectiveness Outcomes, Hemodynamics, Effective Orifice Area: Full-Root Technique All patients analyzed: N=178,

number in subgroup/N, mean ± SD [min., max.]

Endpoint 1 Year 4 Years 8 Years 10 Years Effective Orifice Area

(cm2)

19 mm 7/8, 1.2 ± 0.3

[0.9, 1.7]

21 mm 16/22, 1.4 ± 0.3

[0.9, 1.9]

23 mm 25/33, 1.7 ± 0.4

[1.0, 2.7]

25 mm 33/35, 2.1 ± 0.5

[1.3, 3.5]

27 mm 54/64, 2.4 ± 0.6

[1.3, 4.3]

29 mm 12/16, 2.7 ± 1.0

[1.7, 5.3]

Table 41. Effectiveness Outcomes, Hemodynamics, Effective Orifice Area: Root-Inclusion Technique All patients analyzed:

N=38, number in subgroup/N, mean ± SD [min., max.]

Endpoint 1 Year 4 Years 8 Years 10 Years Effective Orifice Area

(cm2)

19 mm -- -- -- -21 mm 3/4, 1.4 ± 0.3

[1.2, 1.8]

23 mm 9/11, 1.8 ± 0.4

[1.1, 2.2]

25 mm 9/13, 2.0 ± 0.7

[1.0, 3.0]

27 mm 8/10, 2.8 ± 1.1

[1.7, 5.0]

29 mm -- -- -- --

5/8, 1.2 ± 0.2

[0.8, 1.4]

12/22, 1.4 ± 0.4

[0.8, 2.1]

17/33, 1.4 ± 0.2

[1.0, 1.7]

25/35, 2.0 ± 0.3

[1.5, 2.6]

41/64, 2.3 ± 0.6

[1.3, 3.6]

1/16, 2.9 ± --

[2.9, 2.9]

3/4, 1.3 ± 0.4

[0.9, 1.7]

9/11, 1.7 ± 0.3

[1.4, 2.1]

10/13, 2.0 ± 0.7

[1.3, 3.3]

8/10, 2.3 ± 0.6

[1.6, 3.1]

3/8, 1.2 ± 0.4

[0.8, 1.5]

4/22, 1.4 ± 0.7

[0.8, 2.5]

6/33, 1.7 ± 0.5

[1.3, 2.5]

11/35, 1.9 ± 0.3

[1.3, 2.5]

13/64, 2.5 ± 0.7

[1.0, 3.6]

0/16, --

[--]

1/4, 1.0 ± --

[1.0, 1.0]

4/11, 1.5 ± 0.3

[1.3, 1.9]

5/13, 2.1 ± 0.5

[1.4, 2.5]

4/10, 2.0 ± 0.3

[1.6, 2.3]

1/8, 1.2 ± --

[1.2, 1.2]

1/22, 0.8 ± --

[0.8, 0.8]

2/33, 1.3 ± 0.1

[1.3, 1.4]

4/35, 1.6 ± 0.2

[1.3, 1.8]

5/64, 1.9 ± 0.9

[1.1, 3.2]

0/16, --

[--]

0/4, --

[--]

2/11, 1.5 ± 0.3

[1.3, 1.7]

2/13, 1.9 ± 1.2

[1.1, 2.8]

4/10, 1.6 ± 0.3

[1.2, 1.8]

7. Individualization of treatment

Consider long-term anticoagulant or antiplatelet therapy for patients with a dilated left atrium, a history of thromboembolic events, or a cardiac rhythm of atrial fibrillation or atrial flutter.

7.1. Specific patient populations

The safety and effectiveness of the Freestyle bioprosthesis has not been established for the following specific populations because it has not been studied in these populations:

■

Patients in whom the Freestyle bioprosthesis has been implanted for longer than 3 years (sections 5 and 6, Adverse Events and Clinical Studies)

■

Patients who are pregnant

■

Patients who are breast-feeding

■

Patients with chronic renal failure

■

Patients with aneurysmal aortic degenerative conditions (for example, cystic medial necrosis, Marfan’s Syndrome)

The clinical study of the Freestyle bioprosthesis has yielded limited data for the following implant techniques and sizes:

■

Full-Root implant technique in the 19 mm, 21 mm and 23 mm sizes (sections 5 and 6, Adverse Events and Clinical Studies)

■

Root-inclusion implant technique in the 19 mm and 21 mm sizes (sections 5 and 6, Adverse Events and Clinical Studies)

8. Patient counseling information

Patients may require anticoagulation or antiplatelet therapy for an indefinite period based on each patient’s condition. Patients with bioprostheses are at risk for bacteremia (for example, undergoing dental procedures) and should be advised

about prophylactic antibiotic therapy.

22 Instructions for Use English

Page 25

Encourage patients to carry the implanted Device Identification Card, provided by Medtronic, with them at all times.

9. How supplied

9.1. Available sizes

The Freestyle bioprosthesis is designed only for the aortic position and is available in the following sizes: 19 mm, 21 mm, 23 mm, 25 mm, 27 mm, and 29 mm.

9.2. Packaging

The Freestyle bioprosthesis is chemically sterilized and is supplied sterile in a buffered 0.2% glutaraldehyde storage solution. Sterility is compromised if the glass jar and lid container is opened or damaged. The outside of the container is not sterile and should not be placed in the sterile field.

9.3. Storage

Store the Freestyle bioprosthesis between 5° and 25°C (41° and 77°F). Refrigeration is not required, and freezing may damage the bioprosthesis. Room temperature storage up to 25°C (77°F) is satisfactory provided the bioprosthesis is not exposed to sunlight or other ultraviolet light sources or placed where significant temperature fluctuations may occur.

Maintain appropriate inventory control so that bioprostheses with earlier use-by dates are preferentially implanted first to avoid expiration dates.

10. Instructions for use

10.1. Physician training

The function of a stentless bioprosthetic valve is sensitive to surgical implantation technique. The Freestyle bioprosthesis is packaged as a single device that is modified at operation for insertion with 1 of 3 techniques to replace the native valve leaflets with the subcoronary technique, to replace the entire valve mechanism with the root-inclusion technique, or to replace the entire valve mechanism as well as the aortic root with the full-root technique.

Implanting physicians must be familiar with the techniques for implanting an unstented bioprosthesis. These techniques are similar to those required for allograft implantation. Medtronic has established a training program that provides surgeons with instructions on the implantation of the Freestyle bioprosthesis. Contact Medtronic or a local sales representative for further information regarding this program.

10.2. Device features

The Freestyle bioprosthesis features surgeon’s flags, which are located 120 degrees apart at the inflow aspect of the bioprosthesis to facilitate uniform placement of stitches for the proximal suture line. Colored stitching, circumferentially placed around the cloth cover, indicates the upper limit for insertion of the proximal sutures. The size of the bioprosthesis is determined by the outside diameter at the inflow edge. The Freestyle bioprosthesis is designed only for the aortic position and is available in the following sizes: 19 mm, 21 mm, 23 mm, 25 mm, 27 mm, and 29 mm.

10.3. Handling and preparation instructions

Proper size selection of the bioprosthesis is critical to heart valve replacement. The internal diameter of the patient’s aortic root at the annulus and supracommissural areas may be measured preoperatively or during diastole, using angiographic or echocardiographic techniques. Use Freestyle™ aortic obturators, Model 7990, to select the appropriately sized bioprosthesis. For further information refer to the Freestyle aortic obturators Instructions for Use.

Within the sterile operative field, prepare 3 rinse basins, each containing 500 mL of sterile isotonic saline solution. The exterior of the device container and lid are nonsterile. Examine the tamper strips to verify that the container has not been

damaged or previously opened. Do not use if all the tamper strips are damaged. Turn the lid counterclockwise, and open the container (Figure 1).

Do not resterilize the valve by any method. Exposure of the bioprosthesis and container to irradiation, steam, ethylene oxide or other chemical sterilants will render the bioprosthesis unfit for use.

The bioprosthesis and all internal packaging components within the container are sterile and must be handled accordingly. With the thumb and index finger, grasp the retainer and slowly lift the bioprosthesis out of the container allowing for drainage of the glutaraldehyde storage solution (Figure 2).

Open the cap from the valve retainer body and place the valve directly into the free hand (Figure 3 and Figure 4). Record the valve identification number in the patient’s record. Carefully cut the identification tag from the bioprosthesis and discard the tag (Figure 5). Note: Be careful not to cut the cloth or valve tissue when removing the identification tag. Remove any remnants of the

identification tag suture from the bioprosthesis.

Instructions for Use English 23

Page 26

Submerge the bioprosthesis into the first rinse basin. Do not touch the valve leaflets or squeeze the bioprosthesis during the rinsing procedure. Gently swirl the bioprosthesis in the solution for a minimum of 2 minutes in each of the 3 rinse basins (Figure 6). The bioprosthesis should remain in the third rinse basin until required by the surgeon.

10.4. Device implantation

The total root design of the Freestyle bioprosthesis allows the physician to select a bioprosthesis configuration that meets patient indications and surgical technique preference. The provided information reflects the implant techniques utilized during the clinical study:

Subcoronary technique: The native aortic valve is excised for subcoronary implantation of the bioprosthesis. The bioprosthesis is trimmed of excess aorta. The coronary sinuses are scalloped for clearance of native coronary ostia commencing at the sinotubular junction. A sinus may be left intact on the bioprosthesis for a modified subcoronary technique.

Full-root technique: The entire native aortic root and aortic leaflets are excised and replaced with the Freestyle bioprosthesis. The native coronary arteries are excised from the aortic root along with a button of the proximal aorta. The bioprosthesis is sutured to the annulus and 2 of the 3 bioprosthetic sinuses are excised to accommodate the reattachment of the native coronary arteries.

Root-inclusion technique: After the native aortic valve leaflets are excised, the bioprosthesis is placed within the native aorta, giving the appearance of a tube within the native aorta. To allow clearance for the native coronary ostia, 2 of the 3 sinuses are excised leaving buttonholes in the bioprosthesis. The sinotubular junction remains intact. Note: Safety and effectiveness data, from the clinical study, are not available for the 19 mm and 21 mm sizes utilizing the root inclusion technique (sections 5 and 6, Adverse Events and Clinical Studies).

Care should be exercised when placing sutures through the sewing rim and aortic wall to prevent stitching through, or perforation of, the valve cusps. The colored suture line at the inflow identifies the area for placing sutures in the sewing rim. Sutures should only be placed proximal to this demarcation line.

The use of pledgets anywhere within the interior aspect of the bioprosthesis is not recommended. During implantation, periodically irrigate the valve with sterile normal saline to prevent drying of the delicate valve tissue. Do not use cutting needles as they could cause structural damage to the bioprosthesis. Take care not to evert (roll outward) the inflow end of the bioprosthesis when suturing the valve to the patient’s annulus.

Eversion could damage the valve tissue. The potential for damage to the bioprosthesis should be considered before passing surgical instruments through the valve. Root inclusion or subcoronary technique: In some patients, the height of the cloth covering the right muscle bar may

exceed the height of the origin of the patient’s right coronary. Forcing the bioprosthesis to fit in this situation could cause buckling or distortion of the porcine leaflets or aortic wall. Rotation of the bioprosthesis in such cases may be necessary. In the event of rotation, the noncoronary sinus must be trimmed. Use caution when trimming the noncoronary sinus to avoid damage to the valve leaflets.

Use extreme caution if tailoring the bioprosthesis to fit the anatomical requirements of a particular patient’s coronary sinuses or ostia. Improper trimming may result in immediate or delayed damage to or dysfunction of the bioprosthesis.

If the bioprosthetic root is tailored to accommodate the coronary ostia, retained commissure posts should be fixed to the patient’s aortic root 2 to 3 mm above the native commissure attachments to prevent leaflet prolapse and aortic regurgitation.

10.5. Catheterization

Passage of a catheter through any bioprosthesis may damage the valve and is, therefore, not recommended.

10.6. Accessories

Use only Freestyle aortic obturators, Model 7990, and the Medtronic valve handle, Model 7639, to determine the appropriate Freestyle bioprosthesis size.

Caution: Do not use the accessories until they have been thoroughly cleaned and sterilized. Refer to the appropriate Instructions for Use for further instructions.

Caution: Do not use other manufacturers’ valve obturators, or obturators for another Medtronic prosthesis to size the Freestyle bioprosthesis.

11. Postoperative information

11.1. MRI safety information

The Freestyle bioprosthesis is magnetic resonance (MR) Safe. The device will not cause any harm to the patient when exposed to MR scanning immediately after implantation.

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11.2. Return of explanted bioprostheses

Medtronic is interested in obtaining recovered Freestyle bioprosthesis. When determined to be appropriate, explants will be studied by a consulting pathologist. A written report summarizing the findings will be returned to the physician. Product return kits, including an explant information form, are available by contacting Medtronic distribution centers or a Medtronic sales representative. It is important that the explant form be completely filled out. If a kit is not available, place the explanted bioprosthesis in a container of glutaraldehyde or 10% buffered formalin immediately after excision. For further instructions on the return of an explanted device, contact a Medtronic sales representative.

12. Patient information

12.1. Registration information

Note: Patient registration does not apply in countries where patient privacy laws conflict with providing patient information,

including countries from the European Union. A Patient Registration Form is included in each device package. After implantation, please complete all requested information.

The serial number may be found on the package and on the identification tag attached to the bioprosthesis. Return the original form to the Medtronic address indicated on the form and provide the temporary identification card to the patient prior to discharge.

An Implanted Device Identification Card is provided to the patient. The card contains the name and telephone number of the patient’s physician as well as information that medical personnel would require in the event of an emergency.

12.2. Patient manual

Medtronic has prepared a Patient Information Pamphlet that the physician should provide to the patient prior to discharge. Copies of these pamphlets may be obtained from a Medtronic sales representative.

13. Disclaimer of warranty

THE FOLLOWING DISCLAIMER OF WARRANTY APPLIES TO UNITED STATES CUSTOMERS ONLY:

ALTHOUGH THE FREESTYLE BIOPROSTHESES, MODEL 995, HEREAFTER REFERRED TO AS “PRODUCT,” HAVE BEEN MANUFACTURED UNDER CAREFULLY CONTROLLED CONDITIONS, MEDTRONIC HAS NO CONTROL OVER THE CONDITIONS UNDER WHICH THIS PRODUCT IS USED. MEDTRONIC THEREFORE DISCLAIMS ALL WARRANTIES, BOTH EXPRESS AND IMPLIED, WITH RESPECT TO THE PRODUCT, INCLUDING, BUT NOT LIMITED TO, ANY IMPLIED WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. MEDTRONIC SHALL NOT BE LIABLE TO ANY PERSON OR ENTITY FOR ANY MEDICAL EXPENSES OR ANY DIRECT, INCIDENTAL, OR CONSEQUENTIAL DAMAGES CAUSED BY ANY USE, DEFECT, FAILURE, OR MALFUNCTION OF THE PRODUCT, WHETHER A CLAIM FOR SUCH DAMAGES IS BASED UPON WARRANTY, CONTRACT, TORT, OR OTHERWISE. NO PERSON HAS ANY AUTHORITY TO BIND MEDTRONIC TO ANY REPRESENTATION OR WARRANTY WITH RESPECT TO THE PRODUCT.

The exclusions and limitations set out above are not intended to, and should not be construed so as to contravene mandatory provisions of applicable law. If any part or term of this DISCLAIMER OF WARRANTY is held to be illegal, unenforceable, or in conflict with applicable law by a court of competent jurisdiction, the validity of the remaining portions of this DISCLAIMER OF WARRANTY shall not be affected, and all rights and obligations shall be construed and enforced as if this DISCLAIMER OF WARRANTY did not contain the particular part or term held to be invalid.

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Medtronic, Inc.

*1220019001*

710 Medtronic Parkway Minneapolis, MN 55432 USA www.medtronic.com +1 763 514 4000 LifeLine Technical Support, 24-hour consultation service: 1 877 526 7890

Medtronic Heart Valves Division 1851 E. Deere Avenue Santa Ana, CA 92705 USA

Medtronic B.V. Earl Bakkenstraat 10 6422 PJ Heerlen The Netherlands +31 45 566 8000

Canada

Medtronic of Canada Ltd 99 Hereford Street Brampton, Ontario L6Y 0R3 Canada 1 800 268 5346