Atellica® IM High-Sensitivity Troponin I (TnIH)

K241165 · Siemens Healthcare Diagnostics, Inc. · MMI · Jul 25, 2024 · Clinical Chemistry

Device Facts

• Record ID: K241165
• Device Name: Atellica® IM High-Sensitivity Troponin I (TnIH)
• Applicant: Siemens Healthcare Diagnostics, Inc.
• Product Code: MMI · Clinical Chemistry
• Decision Date: Jul 25, 2024
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 862.1215
• Device Class: Class 2
• Attributes: AI/ML

AI Performance

Output	Acceptance	Observed	Dev DS	Test DS
Prognosis for 30-day all-cause mortality (ACM) and major adverse cardiac events (MACE)	Not specified	Lithium Heparin: Post-test risk 9.5% (95% CI: 5.9, 14.8) for >99th percentile; Unadjusted Hazard Ratio 1.61 (95% CI: 0.87, 2.98). Serum: Post-test risk 10.7% (95% CI: 6.8, 16.3) for >99th percentile; Unadjusted Hazard Ratio 1.82 (95% CI: 1.00, 3.32).	Not applicable	Clinical cohort of patients presenting to the emergency department with signs and symptoms suggestive of ACS (N=874 for Lithium Heparin, N=883 for Serum in Cohort A).
Prognosis for 90-day all-cause mortality (ACM) and major adverse cardiac events (MACE)	Not specified	Lithium Heparin: Post-test risk 26.3% (95% CI: 20.4, 33.2) for >99th percentile; Unadjusted Hazard Ratio 2.24 (95% CI: 1.52, 3.29). Serum: Post-test risk 26.7% (95% CI: 20.2, 32.9) for >99th percentile; Unadjusted Hazard Ratio 2.31 (95% CI: 1.57, 3.41).	Not applicable	Clinical cohort of patients presenting to the emergency department with signs and symptoms suggestive of ACS (N=874 for Lithium Heparin, N=883 for Serum in Cohort A).
Prognosis for 182-day all-cause mortality (ACM) and major adverse cardiac events (MACE)	Not specified	Lithium Heparin: Post-test risk 35.8% (95% CI: 29.0, 43.2) for >99th percentile; Unadjusted Hazard Ratio 2.09 (95% CI: 1.51, 2.90). Serum: Post-test risk 36.6% (95% CI: 29.0, 43.2) for >99th percentile; Unadjusted Hazard Ratio 2.16 (95% CI: 1.56, 3.00).	Not applicable	Clinical cohort of patients presenting to the emergency department with signs and symptoms suggestive of ACS (N=874 for Lithium Heparin, N=883 for Serum in Cohort A).
Prognosis for 365-day all-cause mortality (ACM) and major adverse cardiac events (MACE)	Not specified	Lithium Heparin: Post-test risk 48.9% (95% CI: 41.4, 56.4) for >99th percentile; Unadjusted Hazard Ratio 2.21 (95% CI: 1.67, 2.92). Serum: Post-test risk 49.6% (95% CI: 41.5, 56.5) for >99th percentile; Unadjusted Hazard Ratio 2.25 (95% CI: 1.70, 2.98).	Not applicable	Clinical cohort of patients presenting to the emergency department with signs and symptoms suggestive of ACS (N=874 for Lithium Heparin, N=883 for Serum in Cohort A).

Intended Use

The Atellica® IM High-Sensitivity Troponin I (TnIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human serum or plasma (lithium heparin) using the Atellica® IM Analyzer. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI). The Atellica IM TnIH assay can be used as an aid in prognosis for 30-, 90-, 182-, and 365-day all-cause mortality (ACM) and major adverse cardiac events (MACE) in patients presenting with signs and symptoms suggestive of acute coronary syndrome (ACS). MACE consists of myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization.

Device Story

Atellica® IM TnIH assay is a 3-site sandwich immunoassay using direct chemiluminescent technology; inputs are human serum or lithium heparin plasma samples. Solid phase reagent uses streptavidin-coated magnetic particles with biotinylated capture monoclonal antibodies; Lite Reagent uses acridinium ester-labeled recombinant anti-human cTnI sheep Fab. System detects relative light units (RLUs) proportional to cTnI concentration. Used in clinical laboratories on Atellica® IM Analyzer; operated by licensed healthcare professionals. Output is quantitative cTnI concentration; used by clinicians to aid in AMI diagnosis and risk stratification for ACM/MACE in ACS patients. Prognostic utility helps identify patients at higher risk of adverse cardiac events, potentially informing clinical management and monitoring decisions.

Clinical Evidence

Clinical study evaluated prognostic utility in ED patients with ACS symptoms (N=2064). Patients followed for 30, 90, 182, and 365 days for ACM/MACE. Hazard ratios calculated for baseline cTnI levels above vs. below 99th percentile. Results showed higher risk of ACM/MACE for patients with cTnI > 99th percentile. Adjusted hazard ratios for 365-day ACM/MACE were 1.85 (95% CI: 1.39, 2.47) for the total population.

Technological Characteristics

Chemiluminescence sandwich immunoassay; quantitative measurement of cardiac troponin I. Analyzed on Atellica IM Analyzer. Specimen types: serum and lithium heparin plasma. Measuring range: 2.50–25,000.00 pg/mL. Calibration: 2-point. No changes to analytical performance characteristics (precision, linearity, specificity, traceability) since K171566.

Indications for Use

Indicated for quantitative measurement of cardiac troponin I in human serum or lithium heparin plasma to aid in diagnosis of acute myocardial infarction (AMI) and as an aid in prognosis for 30-, 182-, and 365-day all-cause mortality (ACM) and major adverse cardiac events (MACE) in patients presenting with signs and symptoms suggestive of acute coronary syndrome (ACS).

Regulatory Classification

Identification

A creatine phosphokinase/creatine kinase or isoenzymes test system is a device intended to measure the activity of the enzyme creatine phosphokinase or its isoenzymes (a group of enzymes with similar biological activity) in plasma and serum. Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.

Predicate Devices

• VITROS Troponin I ES Assay (K062838)

Submission Summary (Full Text)

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FDA U.S. FOOD & DRUG ADMINISTRATION

# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

A 510(k) Number

K241165

B Applicant

Siemens Healthcare Diagnostics Inc.

C Proprietary and Established Names

Atellica® IM High-Sensitivity Troponin I (TnIH)

D Regulatory Information

| Product Code | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| MMI | Class II | 21 CFR 862.1215 - Creatine Phosphokinase/Creatine Kinase Or Isoenzymes Test System | CH - Clinical Chemistry |

## II Submission/Device Overview:

A Purpose for Submission:

Modification to the indications for use for the Atellica IM High-Sensitivity Troponin I (TnIH) assay cleared in K171566.

B Measurand:

Cardiac troponin I (cTnI)

C Type of Test:

Quantitative immunoassay

Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

www.fda.gov

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K241165 - Page 2 of 15

# III Intended Use/Indications for Use:

## A Intended Use(s):
See Indications for Use below.

## B Indication(s) for Use:
The Atellica® IM High-Sensitivity Troponin I (TnIH) assay is for in vitro diagnostic use in the quantitative measurement of cardiac troponin I in human serum or plasma (lithium heparin) using the Atellica® IM Analyzer. The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI).

The Atellica IM TnIH assay can be used as an aid in prognosis for 30-, 90-, 182-, and 365-day all-cause mortality (ACM) and major adverse cardiac events (MACE) in patients presenting with signs and symptoms suggestive of acute coronary syndrome (ACS). MACE consists of myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization.

## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only

For *in vitro* diagnostic use

## D Special Instrument Requirements:
Atellica IM Analyzer

# IV Device/System Characteristics:

## A Device Description:
The Atellica IM High-Sensitivity Troponin I (TnIH) assay was described in K171566.

## B Principle of Operation:
The principle of operation for the Atellica IM High-Sensitivity Troponin I (TnIH) assay was described in K171566.

# V Substantial Equivalence Information:

## A Predicate Device Name(s):
VITROS Immunodiagnostic Products Troponin I ES Reagent Pack

## B Predicate 510(k) Number(s):
K062838

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C Comparison with Predicate(s):

| Device & Predicate Device(s): | Candidate Device K241165 | Predicate Device K062838 |
| --- | --- | --- |
| Device Trade Name | Atellica® IM High-Sensitivity Troponin I (TnIH) | VITROS Immunodiagnostic Products Troponin I ES Reagent Pack |
| General Device Characteristic Similarities | | |
| Intended Use/Indications For Use | The assay can be used to aid in the diagnosis of acute myocardial infarction (AMI). | Same |
| Detection Technology | Chemiluminescence | Same |
| Type of Immunoassay | Sandwich Immunoassay | Same |
| Analyte | Cardiac Troponin I | Same |
| General Device Characteristic Differences | | |
| Intended Use/Indications For Use | The assay can be used as an aid in prognosis for 30-, 90-, 182-, and 365-day all-cause mortality (ACM) and major adverse cardiac events (MACE) in patients presenting with signs and symptoms suggestive of acute coronary syndrome (ACS). MACE consists of myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization | For the quantitative measurement of cardiac Troponin I (cTnI) in human serum and plasma (heparin and EDTA) using the VITROS Immunodiagnostic System, to aid in the assessment of myocardial damage and risk stratification. Aids in the risk stratification of patients with non-ST-segment elevation acute coronary syndromes with respect to relative risk of mortality, myocardial infarction (MI) or increased probability of ischemic events requiring urgent revascularization procedures. |
| Specimen Type | Serum and lithium heparin plasma | Serum, lithium heparin plasma, and EDTA plasma |
| Measuring Range | 2.50–25,000.00 pg/mL | 12-80,000 pg/mL |
| Upper 99th Percentile Cutoff | Lithium Heparin: Female: 34.11 pg/mL Male: 53.48 pg/mL | 34 pg/mL AMI Diagnostic Cutoff 120 pg/mL |

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| Device & Predicate Device(s): | Candidate Device K241165 | Predicate Device K062838 |
| --- | --- | --- |
| | Combined: 45.20 pg/mL
Serum:
Female: 38.64 pg/mL
Male: 53.53 pg/mL
Combined: 45.43 pg/mL
Overall: 45.20 pg/mL | |
| Calibration | 2-point calibration | 3 levels |

VI Standards/Guidance Documents Referenced:

Not Applicable

VII Performance Characteristics (if/when applicable):

A Analytical Performance:

1. Precision/Reproducibility:
The precision of the Atellica IM High-Sensitivity Troponin I (TnIH) assay was established in K171566.

2. Linearity:
The linearity of the Atellica IM High-Sensitivity Troponin I (TnIH) assay was established in K171566.

3. Analytical Specificity/Interference:
The analytical specificity/interference of the Atellica IM High-Sensitivity Troponin I (TnIH) assay was established in K171566.

4. Assay Reportable Range:
The reportable range of the Atellica IM High-Sensitivity Troponin I (TnIH) assay was established in K171566.

5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
The traceability, sample stability, and expected values of the Atellica IM High-Sensitivity Troponin I (TnIH) assay are unchanged since K171566.

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6. Detection Limit:

The detection limit of the Atellica IM High-Sensitivity Troponin I (TnIH) assay was established in K171566.

7. Assay Cut-Off:

The assay cut-off of the Atellica IM High-Sensitivity Troponin I (TnIH) assay was established in K171566.

B Comparison Studies:

1. Method Comparison with Predicate Device:

Not applicable.

2. Matrix Comparison:

Not applicable. All performance studies in K171566 were performed in all applicable matrices (lithium heparin plasma and serum).

C Clinical Studies:

1. Clinical Sensitivity:

The clinical sensitivity of the Atellica IM High-Sensitivity Troponin I (TnIH) assay as an aid in the diagnosis of AMI was established in K171566.

2. Clinical Specificity:

The clinical specificity of the Atellica IM High-Sensitivity Troponin I (TnIH) assay as an aid in the diagnosis of AMI was established in K171566.

3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):

A clinical study was performed to evaluate the prognostic performance of the device using the same clinical cohort described in K171566. Patients presenting to the emergency department with signs and symptoms suggestive of ACS were followed up for 30-, 90-, 182-, and 365-day progression to ACM and MACE (consisting of myocardial infarction, urgent revascularization, cardiac death, or heart failure hospitalization). At each time point, the risk (cumulative incidence) and hazard ratios were calculated for populations with baseline cardiac troponin I levels ≤ or > the overall 99th percentile value. Lithium heparin plasma and serum specimens were collected and baseline cardiac troponin I levels were established using the Atellica IM Analyzer testing the first blood draw for each subject presenting to the emergency department. The median time of the first blood draw was 93 minutes after presentation to the emergency department.

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Kaplan-Meier curves were generated to display the absolute risk (cumulative incidence) of ACM and MACE outcomes. Analyses were performed separately for both serum and lithium heparin plasma sample types using the overall 99th percentile value. Tables for pre- and post-test risk and unadjusted hazard ratios, adjusted hazard ratios (adjusted for prior revascularization, prior heart failure, estimated glomerular filtration rate (eGFR), hypertension and sex), multivariable Cox proportional hazards (PH) model parameters, and event types, as well as Kaplan-Meier curves, are presented for the following populations based on the overall 99th percentile value. Smoking, diabetes, Body Mass Index (BMI), race, and age were also evaluated and were not significantly associated with cumulative ACM/MACE for any cohort in this clinical population. Prior MI, statins, and depressed left ventricular ejection fraction (LVEF) were evaluated and removed from the model due to multicollinearity. The cohorts and results are summarized below.

- Cohort A: Study population excluding subjects with adjudicated AMI and only including subjects with prior history of MACE
- Cohort B: Study population excluding subjects with adjudicated AMI and prior history of MACE
- Cohort C: Study population excluding subjects with adjudicated AMI

Cohort A (Study population excluding subjects with adjudicated AMI and only including subjects with prior history of MACE)

Overall 99th percentile = 45.20 pg/mL for overall (both lithium heparin and serum samples for males and females combined

Pre- and Post-Test Risk and Unadjusted Hazard Ratios

| Follow-Up Time Points (Days) | Prevalence of ACM/MACE | | | Risk of ACM/MACE for patients with cTnI levels >99th Percentile | | | Risk of ACM/MACE for patients with cTnI levels ≤99th Percentile | | | Unadjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | Number of ACM/MACE events | Pre-test risk of ACM/MACE (%) | N | Number of ACM/MACE events | Post-test risk of ACM/MACE (%, 95% CI) | N | Number of ACM/MACE events | Post-test risk of ACM/MACE (%, 95% CI) | |
| Lithium Heparin | | | | | | | | | | |
| 30 Days | 874 | 58 | 6.6 | 137 | 13 | 9.5 (5.9, 14.8) | 737 | 45 | 6.1 (5.3, 7.0) | 1.61 (0.87, 2.98) |
| 90 Days | 874 | 129 | 14.8 | 137 | 36 | 26.3 (20.4, 33.2) | 737 | 93 | 12.6 (11.4, 13.9) | 2.24 (1.52, 3.29) |
| 182 Days | 874 | 190 | 21.7 | 137 | 49 | 35.8 (29.0, 43.2) | 737 | 141 | 19.1 (17.8, 20.5) | 2.09 (1.51, 2.90) |
| 365 Days | 874 | 259 | 29.6 | 137 | 67 | 48.9 (41.4, 56.4) | 737 | 192 | 26.1 (24.6, 27.6) | 2.21 (1.67, 2.92) |
| Serum | | | | | | | | | | |
| 30 Days | 883 | 60 | 6.8 | 131 | 14 | 10.7 (6.8, 16.3) | 752 | 46 | 6.1 (5.3, 7.0) | 1.82 (1.00, 3.32) |

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| Follow-Up Time Points (Days) | Prevalence of ACM/MACE | | | Risk of ACM/MACE for patients with cTnI levels >99th Percentile | | | Risk of ACM/MACE for patients with cTnI levels ≤99th Percentile | | | Unadjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | Number of ACM/MACE events | Pre-test risk of ACM/MACE (%) | N | Number of ACM/MACE events | Post-test risk of ACM/MACE (%, 95% CI) | N | Number of ACM/MACE events | Post-test risk of ACM/MACE (%, 95% CI) | |
| 90 Days | 883 | 129 | 14.6 | 131 | 35 | 26.7 (20.2, 32.9) | 752 | 94 | 12.5 (11.3, 13.8) | 2.31 (1.57, 3.41) |
| 182 Days | 883 | 192 | 21.7 | 131 | 48 | 36.6 (29.0, 43.2) | 752 | 144 | 19.1 (17.8, 20.5) | 2.16 (1.56, 3.00) |
| 365 Days | 883 | 262 | 29.7 | 131 | 65 | 49.6 (41.5, 56.5) | 752 | 197 | 26.2 (24.6, 27.6) | 2.25 (1.70, 2.98) |

Adjusted Hazard Ratios

| Sample Matrix | Time Point | N | Adjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- |
| Lithium Heparin Plasma | 30 Days | 799 | 1.07 (0.54, 2.09) |
| | 90 Days | 799 | 1.61 (1.06, 2.45) |
| | 182 Days | 799 | 1.59 (1.12, 2.26) |
| | 365 Days | 799 | 1.56 (1.15, 2.12) |
| Sample Matrix | Time Point | N | Adjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- |
| Serum | 30 Days | 807 | 1.31 (0.68, 2.52) |
| | 90 Days | 807 | 1.79 (1.18, 2.71) |
| | 182 Days | 807 | 1.76 (1.24, 2.49) |
| | 365 Days | 807 | 1.70 (1.25, 2.30) |

Summary of Multivariable Cox PH Model Parameters

| | Adjusted hazard ratios (95% CI) | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Follow-Up Time Point | Troponin I | Prior Revascularization | Prior Heart Failure | eGFR | Hypertension | Sex |
| Lithium Heparin | | | | | | |
| 30 days | 1.07 (0.54, 2.09) | 0.64 (0.36, 1.12) | 1.76 (0.96, 3.22) | 1.59 (0.91, 2.79) | 1.16 (0.49, 2.73) | 1.62 (0.89, 2.96) |
| 90 days | 1.61 (1.06, 2.45) | 0.82 (0.56, 1.19) | 2.20 (1.45, 3.32) | 1.52 (1.05, 2.22) | 1.57 (0.82, 3.01) | 1.42 (0.96, 2.11) |
| 182 days | 1.59 (1.12, 2.26) | 0.91 (0.67, 1.24) | 2.19 (1.57, 3.04) | 1.41 (1.03, 1.92) | 1.61 (0.95, 2.74) | 1.28 (0.93, 1.75) |
| 365 days | 1.56 (1.15, 2.12) | 0.91 (0.70, 1.19) | 2.23 (1.68, 2.97) | 1.50 (1.15, 1.96) | 1.54 (0.98, 2.42) | 1.28 (0.98, 1.68) |

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| | Adjusted hazard ratios (95% CI) | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Follow-Up Time Point | Troponin I | Prior Revascularization | Prior Heart Failure | eGFR | Hypertension | Sex |
| Serum | | | | | | |
| 30 days | 1.31 (0.68, 2.52) | 0.62 (0.36, 1.08) | 1.44 (0.81, 2.57) | 1.51 (0.86, 2.63) | 1.20 (0.51, 2.81) | 1.62 (0.89, 2.94) |
| 90 days | 1.79 (1.18, 2.71) | 0.83 (0.57, 1.21) | 1.96 (1.31, 2.94) | 1.53 (1.05, 2.22) | 1.54 (0.81, 2.96) | 1.37 (0.92, 2.02) |
| 182 days | 1.76 (1.24, 2.49) | 0.95 (0.70, 1.29) | 2.16 (1.56, 2.99) | 1.36 (1.00, 1.85) | 1.60 (0.94, 2.71) | 1.28 (0.94, 1.75) |
| 365 days | 1.70 (1.25, 2.30) | 0.95 (0.73, 1.24) | 2.19 (1.65, 2.91) | 1.48 (1.13, 1.93) | 1.53 (0.98, 2.40) | 1.25 (0.96, 1.64) |

Kaplan Meier Failure Plot


Event Types Summary (Lithium Heparin Plasma)

| Type of Event | Total, N=874 (%) | ≤99th Percentile, N=737 (%) | >99th Percentile, N=137 (%) |
| --- | --- | --- | --- |
| Survived to day 365 with no ACM/MACE | 606 | 537 | 69 |
| Loss to follow up | 9 | 8 | 1 |
| ACM/MACE | 259 | 192 | 67 |
| Breakdown of ACM/MACE event | | | |
| Cardiac Death | 10 (3.86) | 9 (4.69) | 1 (1.49) |
| Heart Failure Hospitalization | 163 (62.93) | 113 (58.85) | 50 (74.63) |
| Incident Death | 8 (3.09) | 5 (2.60) | 3 (4.48) |
| Myocardial Infarction | 17 (6.56) | 13 (6.77) | 4 (5.97) |

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| Type of Event | Total, N=874 (%) | ≤99th Percentile, N=737 (%) | >99th Percentile, N=137 (%) |
| --- | --- | --- | --- |
| Survived to day 365 with no ACM/MACE | 606 | 537 | 69 |
| Loss to follow up | 9 | 8 | 1 |
| ACM/MACE | 259 | 192 | 67 |
| Myocardial Infarction, Heart Failure Hospitalization | 2 (0.77) | 1 (0.52) | 1 (1.49) |
| Myocardial Infarction, Urgent Revascularization | 7 (2.70) | 7 (3.65) | 0 (0.00) |
| Myocardial Infarction, Urgent Revascularization, Heart Failure Hospitalization | 1 (0.39) | 1 (0.52) | 0 (0.00) |
| Other Death | 26 (10.04) | 19 (9.90) | 7 (10.45) |
| Urgent Revascularization | 24 (9.27) | 23 (11.98) | 1 (1.49) |
| Urgent Revascularization, Heart Failure Hospitalization | 1 (0.39) | 1 (0.52) | 0 (0.00) |

Cohort B (Study population excluding subjects with adjudicated AMI and prior history of MACE events)

Overall 99th percentile = 45.20 pg/mL for overall (both lithium heparin and serum samples for males and females combined)

Pre- and Post-Test Risk and Unadjusted Hazard Ratios

| Follow-Up Time Points (Days) | Prevalence of ACM/MACE | | | Risk of ACM/MACE for patients with cTnI levels >99th Percentile | | | Risk of ACM/MACE for patients with cTnI levels ≤99th Percentile | | | Unadjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | Number of ACM/MACE events | Pre-test risk of ACM/MACE (%) | N | Number of ACM/MACE events | Post-test risk of ACM/MACE (%, 95% CI) | N | Number of ACM/MACE events | Post-test risk of ACM/MACE (%, 95% CI) | |
| Lithium Heparin | | | | | | | | | | |
| 30 Days | 1190 | 9 | 0.8 | 53 | 3 | 5.7 (2.2, 13.6) | 1137 | 6 | 0.5 (0.3, 0.8) | 10.89 (2.72, 43.53) |
| 90 Days | 1190 | 17 | 1.4 | 53 | 4 | 7.5 (3.2, 16.7) | 1137 | 13 | 1.1 (0.9, 1.5) | 6.84 (2.23, 20.98) |
| 182 Days | 1190 | 37 | 3.1 | 53 | 7 | 13.2 (6.9, 23.9) | 1137 | 30 | 2.6 (2.3, 3.1) | 5.28 (2.32, 12.02) |
| 365 Days | 1190 | 58 | 4.9 | 53 | 8 | 15.1 (8.1, 26.4) | 1137 | 50 | 4.4 (4.0, 4.9) | 3.69 (1.75, 7.79) |

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| Serum | | | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 30 Days | 1214 | 10 | 0.8 | 57 | 2 | 3.5 (1.0, 11.4) | 1157 | 8 | 0.7 (0.5, 0.9) | 5.08 (1.08, 23.94) |
| 90 Days | 1214 | 19 | 1.6 | 57 | 3 | 5.3 (1.9, 13.9) | 1157 | 16 | 1.4 (1.1, 1.7) | 3.87 (1.13, 13.28) |
| 182 Days | 1214 | 39 | 3.2 | 57 | 6 | 10.5 (5.1, 20.5) | 1157 | 33 | 2.9 (2.5, 3.2) | 3.80 (1.59, 9.07) |
| 365 Days | 1214 | 61 | 5.0 | 57 | 7 | 12.3 (6.2, 22.8) | 1157 | 54 | 4.7 (4.3, 5.1) | 2.75 (1.25, 6.05) |

Adjusted Hazard Ratios

| Sample Matrix | Time Point | N | Adjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- |
| Lithium Heparin Plasma | 30 Days | 1169 | 7.46 (1.65, 33.65) |
| | 90 Days | 1169 | 5.58 (1.69, 18.47) |
| | 182 Days | 1169 | 3.89 (1.63, 9.30) |
| | 365 Days | 1169 | 2.79 (1.28, 6.08) |
| Sample Matrix | Time Point | N | Adjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- |
| Serum | 30 Days | 1192 | 2.84 (0.56, 14.38) |
| | 90 Days | 1192 | 2.81 (0.78, 10.12) |
| | 182 Days | 1192 | 2.71 (1.10, 6.69) |
| | 365 Days | 1192 | 2.06 (0.92, 4.64) |

Summary of Multivariable Cox PH Model Parameters

| | Adjusted hazard ratios (95% CI) | | | |
| --- | --- | --- | --- | --- |
| Follow-Up Time Point | Troponin I | eGFR | Hypertension | Sex |
| Lithium Heparin | | | | |
| 30 days | 7.46 (1.65, 33.65) | 2.16 (0.46, 10.08) | 2.07 (0.41, 10.54) | 1.32 (0.35, 4.94) |
| 90 days | 5.58 (1.69, 18.47) | 1.73 (0.51, 5.92) | 1.21 (0.43, 3.41) | 1.52 (0.58, 4.02) |
| 182 days | 3.89 (1.63, 9.30) | 2.41 (1.09, 5.33) | 1.18 (0.58, 2.40) | 1.56 (0.81, 3.00) |
| 365 days | 2.79 (1.28, 6.08) | 2.30 (1.21, 4.40) | 1.20 (0.69, 2.09) | 1.53 (0.90, 2.58) |
| Serum | | | | |
| 30 days | 2.84 (0.56, 14.38) | 4.05 (1.05, 15.68) | 2.28 (0.46, 11.30) | 1.52 (0.43, 5.40) |
| 90 days | 2.81 (0.78, 10.12) | 2.49 (0.84, 7.38) | 1.41 (0.52, 3.85) | 1.43 (0.57, 3.57) |
| 182 days | 2.71 (1.10, 6.69) | 2.89 (1.37, 6.08) | 1.26 (0.63, 2.53) | 1.49 (0.78, 2.82) |
| 365 days | 2.06 (0.92, 4.64) | 2.61 (1.41, 4.84) | 1.19 (0.69, 2.05) | 1.52 (0.91, 2.53) |

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K241165 - Page 11 of 15

Kaplan Meier Failure Plots

*Error bars denote 95% confidence limits.

Event Types Summary (Lithium Heparin Plasma)

| Type of Event | Total, N=1190 (%) | ≤99th percentile, N=1137 (%) | >99th percentile, N=53 (%) |
| --- | --- | --- | --- |
| Survived to day 365 with no ACM/MACE | 1118 | 1073 | 45 |
| Loss to follow up | 14 | 14 | 0 |
| ACM/MACE | 58 | 50 | 8 |
| Breakdown of ACM/MACE Event | | | |
| Cardiac Death | 2 (3.45) | 2 (4.00) | 0 (0.00) |
| Heart Failure Hospitalization | 29 (50.00) | 23 (46.00) | 6 (75.00) |
| Myocardial Infarction | 4 (6.90) | 3 (6.00) | 1 (12.50) |
| Myocardial Infarction, Urgent Revascularization, Cardiac Death | 1 (1.72) | 0 (0.00) | 1 (12.50) |
| Other Death | 14 (24.14) | 14 (28.00) | 0 (0.00) |
| Urgent Revascularization | 8 (13.79) | 8 (16.00) | 0 (0.00) |

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Cohort C (Study population excluding those with adjudicated AMI)

Overall 99th percentile = 45.20 pg/mL for overall (both lithium heparin and serum samples for males and females combined)

Pre- and Post-Test Risk and Unadjusted Hazard Ratios

| Follow-Up Time Points (Days) | Prevalence of ACM/MACE | | | Risk of ACM/MACE for patients with cTnI levels >99th Percentile | | | Risk of ACM/MACE for patients with cTnI levels ≤99th Percentile | | | Unadjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | N | Number of ACM/MACE events | Pre-test risk of ACM/MACE (%) | N | Number of ACM/MACE events | Post-test risk of ACM/MACE (%, 95% CI) | N | Number of ACM/MACE events | Post-test risk of ACM/MACE (%, 95% CI) | |
| Lithium Heparin | | | | | | | | | | |
| 30 Days | 2064 | 67 | 3.2 | 190 | 16 | 8.4 (5.5, 12.6) | 1874 | 51 | 2.7 (2.4, 3.1) | 3.21 (1.83, 5.64) |
| 90 Days | 2064 | 146 | 7.1 | 190 | 40 | 21.1 (16.4, 26.6) | 1874 | 106 | 5.7 (5.1, 6.2) | 4.03 (2.80, 5.80) |
| 182 Days | 2064 | 227 | 11.0 | 190 | 56 | 29.5 (24.0, 35.6) | 1874 | 171 | 9.1 (8.5, 9.8) | 3.66 (2.71, 4.95) |
| 365 Days | 2064 | 317 | 15.4 | 190 | 75 | 39.5 (33.3, 46.0) | 1874 | 242 | 12.9 (12.2, 13.6) | 3.64 (2.81, 4.72) |
| Serum | | | | | | | | | | |
| 30 Days | 2097 | 70 | 3.3 | 188 | 16 | 8.5 (5.6, 12.8) | 1909 | 54 | 2.8 (2.5, 3.2) | 3.13 (1.79, 5.47) |
| 90 Days | 2097 | 148 | 7.1 | 188 | 38 | 20.2 (15.6, 25.8) | 1909 | 110 | 5.8 (5.3, 6.3) | 3.79 (2.62, 5.48) |
| 182 Days | 2097 | 231 | 11.0 | 188 | 54 | 28.7 (23.3, 34.9) | 1909 | 177 | 9.3 (8.7, 9.9) | 3.49 (2.57, 4.74) |
| 365 Days | 2097 | 323 | 15.4 | 188 | 72 | 38.3 (32.2, 44.8) | 1909 | 251 | 13.1 (12.5, 13.8) | 3.44 (2.65, 4.47) |

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Adjusted Troponin I Hazard Ratios

| Sample Matrix | Time Point | N | Adjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- |
| Lithium Heparin Plasma | 30 Days | 1968 | 1.55 (0.84, 2.89) |
| | 90 Days | 1968 | 2.03 (1.36, 3.01) |
| | 182 Days | 1968 | 1.97 (1.42, 2.73) |
| | 365 Days | 1968 | 1.85 (1.39, 2.47) |
| Sample Matrix | Time Point | N | Adjusted Hazard Ratio (95% CI) |
| --- | --- | --- | --- |
| Serum | 30 Days | 1999 | 1.68 (0.91, 3.09) |
| | 90 Days | 1999 | 2.11 (1.42, 3.13) |
| | 182 Days | 1999 | 2.04 (1.48, 2.83) |
| | 365 Days | 1999 | 1.91 (1.44, 2.54) |

Summary of Multivariable Cox PH Model Parameters

| | Adjusted hazard ratios (95% CI) | | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Follow-Up Time Point | Troponin I | Prior Revascularization | Prior Heart Failure | eGFR | Hypertension | Sex |
| Lithium Heparin | | | | | | |
| 30 days | 1.55
(0.84, 2.89) | 1.19
(0.71, 2.02) | 3.62
(2.07, 6.33) | 1.74
(1.02, 2.98) | 1.87
(0.86, 4.05) | 1.62
(0.94, 2.79) |
| 90 days | 2.03
(1.36, 3.01) | 1.39
(0.98, 1.97) | 4.35
(2.96, 6.38) | 1.60
(1.11, 2.29) | 1.93
(1.12, 3.31) | 1.48
(1.03, 2.14) |
| 182 days | 1.97
(1.42, 2.73) | 1.50
(1.13, 1.98) | 3.79
(2.80, 5.12) | 1.56
(1.16, 2.08) | 1.85
(1.23, 2.80) | 1.37
(1.03, 1.82) |
| 365 days | 1.85
(1.39, 2.47) | 1.47
(1.16, 1.88) | 3.80
(2.94, 4.92) | 1.63
(1.27, 2.10) | 1.75
(1.24, 2.45) | 1.37
(1.08, 1.74) |
| Serum | | | | | | |
| 30 days | 1.68
(0.91, 3.09) | 1.22
(0.73, 2.03) | 2.99
(1.74, 5.13) | 1.78
(1.05, 3.02) | 2.05
(0.95, 4.41) | 1.71
(0.99, 2.92) |
| 90 days | 2.11
(1.42, 3.13) | 1.43
(1.01, 2.03) | 3.81
(2.62, 5.55) | 1.65
(1.15, 2.36) | 2.01
(1.17, 3.44) | 1.45
(1.01, 2.07) |
| 182 days | 2.04
(1.48, 2.83) | 1.54
(1.17, 2.03) | 3.66
(2.72, 4.92) | 1.54
(1.15, 2.06) | 1.89
(1.25, 2.85) | 1.38
(1.04, 1.83) |
| 365 days | 1.91
(1.44, 2.54) | 1.52
(1.20, 1.93) | 3.67
(2.85, 4.73) | 1.64
(1.28, 2.10) | 1.73
(1.24, 2.42) | 1.36
(1.07, 1.73) |

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Kaplan Meier Failure Plots


Event Types Summary (Lithium Heparin Plasma)

| Type of Event | Total, N=2064 (%) | ≤99th percentile, N=1874 (%) | >99th percentile, N=190 (%) |
| --- | --- | --- | --- |
| Survived to day 365 with no ACM/MACE | 1724 | 1610 | 114 |
| Loss to follow up | 23 | 22 | 1 |
| ACM/MACE | 317 | 242 | 75 |
| Breakdown of ACM/MACE Event | | | |
| Cardiac Death | 12 (3.79) | 11 (4.55) | 1 (1.33) |
| Heart Failure Hospitalization | 192 (60.57) | 136 (56.20) | 56 (74.67) |
| Incident Death | 8 (2.52) | 5 (2.07) | 3 (4.00) |
| Myocardial Infarction | 21 (6.62) | 16 (6.61) | 5 (6.67) |
| Myocardial Infarction, Heart Failure Hospitalization | 2 (0.63) | 1 (0.41) | 1 (1.33) |
| Myocardial Infarction, Urgent Revascularization | 7 (2.21) | 7 (2.89) | 0 (0.00) |
| Myocardial Infarction, Urgent Revascularization, Cardiac Death | 1 (0.32) | 0 (0.00) | 1 (1.33) |
| Myocardial Infarction, Urgent Revascularization, Heart Failure Hospitalization | 1 (0.32) | 1 (0.41) | 0 (0.00) |

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| Type of Event | Total, N=2064 (%) | ≤99th percentile, N=1874 (%) | >99th percentile, N=190 (%) |
| --- | --- | --- | --- |
| Survived to day 365 with no ACM/MACE | 1724 | 1610 | 114 |
| Loss to follow up | 23 | 22 | 1 |
| ACM/MACE | 317 | 242 | 75 |
| **Breakdown of ACM/MACE Event** | | | |
| Other Death | 40 (12.62) | 33 (13.64) | 7 (9.33) |
| Urgent Revascularization | 24 (10.09) | 23 (12.81) | 1 (1.33) |
| Urgent Revascularization, Heart Failure Hospitalization | 1 (0.32) | 1 (0.41) | 0 (0.00) |

D Clinical Cut-Off:

The clinical cut-off of the Atellica IM High-Sensitivity Troponin I (TnIH) assay was established in K171566.

E Expected Values/Reference Range:

The expected values/reference range of the Atellica IM High-Sensitivity Troponin I (TnIH) assay were established in K171566.

VIII Proposed Labeling:

The labeling supports the finding of substantial equivalence for this device.

IX Conclusion:

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.

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