By Robert Fraser
January 22, 2021
ISO 5840-1, 5840-2, and 5840-3 were published on January 22, 2021. This document highlights changes from previous versions of the standard on select in-vitro testing requirements. Additional major changes, including updates to the pre-clinical and clinical section, are not covered here. A good summary of the ISO 5840 standards can be found here.
The following general changes have been made to part 1 and are applicable to all heart valve types.
-In response to Sub-acute leaflet thrombosis phenomenon that has been observed clinically, there is a new annex in ISO 5840-1 for “Assessment of Implant Thrombogenic and Haemolytic Potential”. Particle Image Velocimetry (PIV) flow visualization, Computational fluid dynamics (CFD) analysis, and blood loops are some of the suggested tests as part of an integrated approach.
-Clarified the terms control valve and reference valve. The term “Control valve” is used for preclinical and clinical evaluations. “Reference valve” is used for in-vitro and pre-clinical evaluations.
-There is a decreased focus on terms “flexible” and “rigid” heart valve substitutes. Focus is now on gradual or catastrophic failure modes.
-The standards have expanded information on Mitral valve testing. There is also more guidance for right heart testing, and pediatric indications. ISO 5840-1:2020 Tables 1 and 2 now show all pressure in terms of ranges. ISO 5840-1 Tables 3 and 4 (and Annex E) give specific testing requirements for in-vitro testing.
-ISO 5840-1:2020 now states that test methods should be validated in accordance with ISO 17025.
-Parts 2 and 3, have dropped the annexes on definitions of physical and material properties as well as standards applicable to materials and component testing. These were not comprehensive and deemed out of scope for this standard.
The following changes to durability testing are applicable to all types of valves.
ISO 5840-1:2020 now presents an “integrated durability assessment” which focuses on determining if there is an immediate total loss of valve function or gradual degradation of valve function. Accelerated wear testing (AWT), dynamic failure mode testing (DFM), and real-time wear testing (RWT) are all elements of this integrated approach. ISO 5840-1:2020 Annex J provides much more detail and is now a normative annex. DFM and RWT testing are brand new sub-sections of this annex.
Test duration is now 400 million cycles for failure modes with immediate total loss of valve function and 200 million cycles for demonstrated gradual degradation. For material types and/or processing methods without established clinical history, testing durations of greater than the minimum required cycle counts shall be considered.
The test now emphasizes the importance of, and focus on, leaflet kinematics.
Sample sizes for surgical valves are 5 test devices plus 1 reference device (if applicable). For transcatheter valves, it is 3 samples of each deployed configuration (ellipticity, minimum deployed size, maximum deployed size). If there is only one deployed condition, then test 5 samples plus 1 reference device (if applicable). A transcatheter valve or surgical valve may be utilized as a reference valve for the durability testing.
For all valves, you need to test all sizes unless scientific justification is provided. In that case, there is a minimum of smallest, intermediate, and largest valve size tested.
There is no long an explicit 95% rule. The manufacturer shall statistically demonstrate that the differential pressure target is maintained for the required minimum number of cycles.
The following covers changes to pulsatile flow applicable to all types of valves.
Contact ViVitro Tech Support to obtain an updated version of ViViTest to comply with the new methods of determining test operating conditions (mainly cardiac output and systolic duration).
-“Simulated Cardiac Output” builds on the 2015 standard and clarifies that this definition is for in-vitro testing. This is calculated using forward flow volume x beat rate.
-ISO 5840-1:2020 has added many more definitions to specify time points in the cardiac cycle. See figures 3 and 4 in ISO 5840-1:2020. These include:
-Diastolic duration, End of Diastole, end of closure, start of diastole, start of leakage, and start of systole.
-Start and End of positive differential pressure has been clarified. The First and second crossing are to be used, respectively.
-Systolic duration – clarified in-vitro definition; this is now based on forward flow.
-Clarified definition of forward flow volume.
-Regurgitant volume, including the closing volume and leakage volume should be reported in milliliters and as a percentage of forward flow volume.
-It is recommended that manufacturers complete pulse duplicator system performance characterization prior to the start of design verification testing.
Specific St. Jude Medical Masters Series mechanical valves may be used for this. Read more about the reference valves here and contact ViVitro Tech Support to order a valve and corresponding certificate.
The following changes are only applicable to transcatheter valves.
ISO 5840-3 now has a specific holder design for aortic valves including a simulated calcification nodule. There are suggestions for mitral valves, but they are largely left to the manufacturer to justify. Contact ViVitro to enquire about assistance with the holder design.
-ISO 5840-1:2020 -New Area derived valve diameter is useful for converting non-circular geometry into a standardized diameter measurement.
-ISO 5840-1:2020 now has provisions for Valve-in-Valve and Valve-in-Ring applications.
-For transcatheter valves, the test sample pre-conditioning steps have been expanded to explicitly state crimping or loading, tracking through simulated delivery pathways, and maintaining in the crimped configuration for a duration that mimics the worst-case expected clinical procedure time.
-ISO 5840-3 has updated hydrodynamic performance requirements. The standard no longer differentiates paravalvular from total regurgitant fraction. Regurgitant fraction acceptance is now 20% across all valve sizes.
ISO 5840-3 Leaflet kinematics are explicitly called out in the test report.
ISO 5840-3 now has terms for the Neo-LVOT and Neo-Sinus.
ISO 5840-3 states the delivery system should resist particulate generation.
ISO 5840-3, Annex B gives an updated hazard analysis table. See additional publication by Iyer R. et al. for information specific to TMVI devices.
ISO 5840-3, Annex D is a new annex for evaluating the delivery system.
The ISO standards committee is very aware that the release of standards often lags behind innovation. Therefore, for the first time, white papers have been used to supplement the standard. These white papers will continue to be published when completed. They will then be incorporated into the standard with the next revision. To date, the white papers include:
Iyer R. et al. Transcatheter Mitral Valve Replacement: Functional Requirements for Device Design, Bench-Top, and Pre-Clinical Evaluation. Cardiovasc Eng Technol. 2018, 9 (3) pp. 301-338.
Raghav V., Sastry S., Saikrishnan N. Experimental Assessment of Flow Fields Associated with Heart Valve Prostheses Using Particle Image Velocimetry (PIV): Recommendations for Best Practices. Cardiovasc Eng Technol. 2018, 9 pp. 273-287.
Wei Z.A. et al. Computational Fluid Dynamics Assessment Associated with Transcatheter Heart Valve Prostheses: A Position Paper of the ISO Working Group. Cardiovasc Eng Technol. 2018, 9 pp. 289-299.
Linde T., Clauser J., Meuris B. et al. Assessing the thrombogenic potential of heart valve prostheses: an approach for a standardized in-vitro method. Cardiovasc Eng Technol. 2019, 10 pp. 216-224.
Wu C. et al. In-Vitro Pulsatile Flow Testing of Prosthetic Heart Valves: A Round-Robin Study by the ISO Cardiac Valves Working Group. Cardiovasc Eng Technol. 2019, 10 pp.397-422.
For the first time, all three ISO 5840 standards have been released together. From an in-vitro testing perspective a new annex on thrombus assessment and a new integrated approach to durability are some of the largest changes. These highlight the importance of Particle Imaging Velocity (PIV) and Real time wear testing (RWT), areas where ViVitro is an industry leader.
ViVitro Labs Applications Manager, Rob Fraser, is a Canadian representative on ISO Technical Committee 150, Subcommittee 2, Working Group 1 Cardiac Valves.