Microsoft Word C034164e doc Reference number ISO 5840 2005(E) © ISO 2005 INTERNATIONAL STANDARD ISO 5840 Fourth edition 2005 03 01 Cardiovascular implants — Cardiac valve prostheses Implants cardiovas[.]
Intended use
The manufacturer shall identify the physiological condition(s) to be treated, the intended patient population, potential adverse events and intended claims.
Design inputs
Operational specifications
The manufacturer must establish clear operational specifications for the device, incorporating its principles of operation, anticipated lifespan, shelf life, and storage or shipping requirements Additionally, these specifications should specify the physiological environment suitable for the device’s intended use Table 1 outlines the expected physiological parameters of the target patient population, covering both normal and pathological conditions for heart valve substitutes, ensuring compliance with safety and efficacy standards.
Table 1 — Heart valve substitute operational environment
Surrounding medium: Human heart/Human blood
Heart rate: 30 beats/min to 200 beats/min
Cardiac output: 3 l/min to 15 l/min
Stroke volume: 25 ml to 100 ml
Differential pressure across closed valve
Blood pressures and resultant pressure loads by patient condition:
Arterial peak systolic pressure mm Hg
Arterial diastolic pressure mm Hg Aortic ∆p A mm Hg
Extreme (expected maximum pressure for a single cycle) 300 160 230 300
Performance specifications
6.2.2.1 The manufacturer shall establish (i.e define, document and implement) the clinical performance requirements of the device and the corresponding device performance specifications The limits for device performance specifications shall be determined by the manufacturer for the specific heart valve substitute design in light of the intended use and claims to be made for the device The following list of desired clinical and device-based performance characteristics describe a safe and effective heart valve substitute
6.2.2.2 Specifications shall be defined in respect of at least the following performance characteristics:
allows forward flow with acceptably small mean pressure difference;
prevents retrograde flow with acceptably small regurgitation;
is compatible with in vivo diagnostic techniques;
is deliverable and implantable in the target population;
has an acceptable noise level;
maintains its functionality for a reasonable lifetime, consistent with its generic class;
maintains its functionality and sterility for a reasonable shelf life prior to implantation.
Packaging, labelling, and sterilization
The heart valve substitute shall meet the requirements for packaging, labelling, and sterilization contained within Annexes P, Q, and S, respectively.
Design outputs
General
The manufacturer must establish and thoroughly document a comprehensive specification for the heart valve substitute, covering component and assembly-level details, accessories, packaging, and labeling A generic block diagram of the heart valve substitute is provided in Figure 3 to illustrate its structure, while Annex I offers standardized terminology for describing different valve models Additionally, subclause 6.3.2 includes examples of typical valve components found in various heart valve substitutes, ensuring clarity and consistency in design and documentation.
Figure 3 — Generic heart valve substitute block diagram
Examples of components of some heart valve substitutes
The following is a listing of examples of typical valve components of some heart valve substitutes The following listing is not meant to be exhaustive
Coating: any thin-film material that is applied to an element of a heart valve substitute in order to modify its physical or chemical properties;
Component-joining materials, such as sutures, adhesives, or welding compounds, are essential for assembling heart valve substitutes These materials become integral parts of the implant device, ensuring secure attachment and functionality (see Figures J.1, J.3, and J.4) Proper selection of these materials is crucial for the durability and safety of the heart valve implant.
covering: any element applied to enclose any other element of the heart valve substitute (see Figures J.1, J.3, J.4 and J.5);
occluder/leaflet: component that inhibits backflow (see Figures J.1, J.2, J.3, J.4 and J.5);
occluder retention mechanism: component(s) of a heart valve substitute which support(s) or retain(s) the occluder(s) (see Figures J.1 and J.2);
orifice ring (also housing): component of a heart valve substitute that houses the occluder(s) of a rigid heart valve (see Figure J.1);
sewing ring (also sewing cuff): component of a heart valve substitute by which it can be attached to the heart (see Figure J.1);
sewing-ring filler: any material within the confines of the sewing ring of the heart valve substitute which provides it with bulk and shape (see Figure J.1);
sewing-ring retaining material: material used to prevent separation of the sewing ring from the orifice ring or frame (see Figures J.1 and J.2);
stent (also frame, body): component of a heart valve substitute that houses the occluder(s) of a flexible leaflet device (see Figure J.5);
stiffening element: component which reduces deformation of the orifice ring or stent (see Figure J.1).
Design transfer (manufacturing qualification)
6.4.1 The manufacturer shall generate a manufacturing flowchart identifying the manufacturing process operations and inspection steps The input of all components and important manufacturing materials shall be indicated on the flowchart
6.4.2 The manufacturer shall document the results of the validation of all special processes and the validation of all process software
As part of the risk management process, manufacturers must establish control measures and process conditions to ensure medical device safety and suitability for its intended use The risk management file should identify and justify verification activities that demonstrate the acceptability of the selected process ranges, ensuring consistent device performance and compliance with safety standards.
6.4.4 The manufacturer shall establish the adequacy of full-scale manufacturing by validation of the manufacturing process
NOTE 1 Refer to Global Harmonization Task Force [10] for further detail on design input, design output, and design transfer
NOTE 2 Refer to Global Harmonization Task Force [11] for further detail on process validation.
Risk management
Hazard identification
Subclause 4.3 of ISO 14971:2000 shall apply The testing and analysis necessary to estimate the risk associated with each hazard shall be determined from information on the nature of the hazard and the corresponding failure modes/causes In identifying known and foreseeable hazards, particular consideration shall be given to hazards associated with failure modes related to design, manufacturing and human factors for each of the four elements identified in Figure 3 Table B.1 contains a list of potential hazards specific to heart valve substitutes which may serve as the basis for a risk analysis.
Failure mode identification
The second and third columns of Table B.1 provide a listing of potential failure modes that may result in the identified hazard A given hazard may result from one or more failure modes; likewise, a given failure mode may result in one or more hazards
Risk estimation
Subclause 4.4 of ISO 14971:2000 shall apply To facilitate risk estimation for identified hazards, verification and validation testing may be used, as defined by the risk management plan The testing outlined in Clause 7 serves as a basis for verification and validation test requirements The last column of Table B.1 contains a list of potential evaluation methods which may facilitate risk estimation through failure mode identification and/or failure probability quantification This list is not intended to be all-inclusive but rather a representative listing of methods that may be applicable to the specified hazard and failure mode The rationale explaining how the tests performed facilitate risk estimation for each identified hazard shall be documented in the risk management file
Examples of risk estimation schemes are given in Annex C.
Risk evaluation
Clause 5 of ISO 14971:2000 shall apply Since acceptable risk levels may not be specified by applicable standards, the manufacturer shall establish and justify the risk acceptance criteria used Any identified risk shall be reduced to a level which is “broadly acceptable” or, if that is not feasible, “as low as reasonably practicable” (ALARP)
Examples of risk evaluation schemes are given in Annex C.
Risk control
Clause 6 of ISO 14971:2000 shall apply The device design and quality assurance requirements, including packaging and labelling specifications, necessary to assure the acceptability of risks, shall be documented in the risk management file.
Risk review
Subclause 7.4.5.2 shall apply This International Standard requires long-term follow-up of a subset of patients included in the clinical evaluation of the heart valve substitute The review of post-production information for relevance to device safety shall include evaluating information from the long-term follow-up as well as other sources of information, such as literature reports, reports to regulatory authorities and field experience reports
7 Verification testing and analysis/Design validation
General requirements
The manufacturer must conduct verification testing to ensure that the heart valve substitute meets its design specifications, confirming that the design output aligns with the input The test program should include tests identified through risk analysis, focusing on hazards related to the device Test protocols must clearly define the purpose, goals, setup, equipment specifications and calibration, test conditions justified by in vivo operating scenarios, acceptance criteria, and the number of samples tested to validate device performance and safety.
The manufacturer shall validate the design of the heart valve substitute, its packaging/labelling, and accessories
In vitro assessment
Test conditions, sample selection and reporting requirements
7.2.1.1 Test conditions and sample selection
Test specimens must closely replicate the condition of the final product intended for clinical use, including exposure to the maximum recommended sterilization cycles when applicable.
When emulating in vivo conditions is relevant to the test method, it is essential to consider the operational specifications outlined in Table 1 (see 6.2.1) Testing should be conducted using a suitable test fluid, such as isotonic saline, blood, or a blood-equivalent fluid, ensuring that its physical properties—like specific gravity and viscosity at working temperatures—are appropriate for the specific test being performed.
The selection of test fluid should be based on the specific test goals, testing methods, and the valve class Additionally, a thorough risk assessment is essential to inform and guide the decision-making process for choosing the appropriate test fluid, ensuring reliable and safe testing outcomes.
A comprehensive test report must include the rationale for conducting the test, detailed identification and description of the tested sample, including batch number, and the reference valve(s) It should specify the number of specimens tested along with the sample size rationale, provide a detailed description of the test method, and confirm that applicable quality assurance standards, such as Good Laboratory Practice, have been met Finally, the report should present clear test results and conclusions to ensure transparency and compliance with quality standards.
Statistical procedures, such as the ones described in Annex E, may be used to assist data analysis.
Material property assessment
Properties of heart valve substitutes and their components shall be evaluated as applicable to the specific design of the valve as determined by the risk assessment
The biocompatibility of materials and components used in heart valve substitutes must be evaluated according to ISO 10993-1, ensuring a thorough biological safety assessment The risk management documentation should include a clear test plan, justifying the appropriateness and completeness of the gathered information, and explaining any supplementary tests or omissions based on ISO guidelines During hazard identification, sufficient data must be collected to recognize potential toxicological risks, including impacts on hematological characteristics For hazards with possible significant clinical effects, toxicological risks should be characterized by analyzing factors such as mode of action, dose-response relationships, exposure levels, biochemical interactions, and toxicokinetics.
For heart valve substitutes using animal tissue or their derivatives, the risk associated with the use of these materials shall be evaluated in accordance with EN 12442-1, -2 and -3
Evaluating the material properties of heart valve substitutes and their components is essential to ensure suitability for specific valve designs Annex D details relevant physical and chemical properties categorized by material class and components, aiding in comprehensive assessment Additionally, Annex K lists applicable testing standards for materials and components, ensuring compliance with quality and safety regulations This systematic evaluation supports the development of safe, effective heart valve replacements aligned with industry standards.
Hydrodynamic performance assessment
Hydrodynamic testing is essential to evaluate the fluid mechanical performance of heart valve substitutes This testing provides critical indicators of how the valve affects cardiac load, as well as its potential to cause blood stasis and damage Such assessments ensure the valve's efficiency and safety, supporting optimal patient outcomes.
A guideline for the performing and reporting of hydrodynamic tests is given in Annex L The detailed protocols shall be based on the findings of the risk assessment
Tests must be conducted on at least three heart valve substitutes per size and on one reference valve for small, medium, and large sizes Alternative sample sizes or size distributions are permitted if risk analysis demonstrates they provide adequate information.
In vitro test results must meet or exceed the minimum performance requirements outlined in Table 2, which are determined based on valve size, TAD, and position These requirements are assessed under pulsatile-flow conditions of a 70 cycles/min beat rate, a simulated cardiac output of 5.0 L/min, a mean aortic pressure of 100 mm Hg, and a systolic duration of 35% The minimum performance standards are established according to values reported in scientific literature to ensure reliability and efficacy.
NOTE See Yoganathan and Travis [26] and Marquez et al [16]
A EO is the effective orifice area in square centimetres; v RMS q is the root mean square forward flow in milliletres per second;
The mean pressure difference (∆p) is measured in millimetres of mercury during the positive pressure phase of the forward flow The test fluid's density (ρ) is expressed in grams per cubic centimetre, which is essential for accurate pressure analysis Understanding these parameters is crucial for precise fluid dynamics assessments and performance testing.
NOTE This equation is derived from the Bernoulli Equation The constant (51,6) is not dimensionless, thus this equation is only valid with the units shown
Structural performance assessment
To ensure the reliability of heart valve substitutes, a thorough assessment of their ability to withstand operational loads is essential This evaluation helps identify potential structural failure modes and associated risks, ensuring the durability and safety of the valve under physiological conditions Proper testing and analysis are crucial steps in verifying that the heart valve can perform effectively without risking failure during use.
An assessment of the durability of heart valve substitutes is essential to ensure their continued function over a reasonable lifespan If the device's labeling does not specify an expected in vivo lifetime, testing must demonstrate that rigid heart valve substitutes can withstand at least 400 million cycles, while flexible substitutes can endure at least 200 million cycles However, if the device’s labeling explicitly states an anticipated in vivo lifetime, testing must support and validate this claim, confirming the device’s long-term performance and reliability.
Testing must be conducted on a minimum of three samples for each size category—largest, medium, and smallest—of both aortic and mitral heart valve substitutes to ensure reliable results Additionally, an equivalent size reference valve should be tested under the same conditions for each valve size to facilitate accurate comparisons This approach guarantees comprehensive evaluation across different valve sizes, supporting validation and quality assurance in heart valve testing protocols.
Durability testing shall be conducted at a specified differential pressure aligned with normotensive conditions outlined in Table 1 The test ensures that the target peak differential pressure across the closed valve is maintained for at least 95% of all test cycles, with each valve experiencing this pressure for at least 5% of each cycle’s duration If aortic and mitral heart valve substitutes have identical designs except for the sewing cuff, testing can be performed under the differential pressure conditions specified for the mitral valve, ensuring consistency in safety and performance evaluation.
Cycle rates for accelerated and quasi-real-time durability testing must be justified based on risk analysis outcomes It is essential to consider the behavior of time-dependent materials when selecting and justifying appropriate cycle rates to ensure accurate and reliable test results.
Test valves must undergo the full range of occluder motion typical of normotensive conditions during testing, as outlined in Table 1 Regular and frequent inspections, such as daily or weekly, are essential when valves are subjected to cycling in durability testers Additionally, valves should be evaluated at intervals of 50 million cycles or less throughout the testing period to ensure continued performance and reliability.
Durability assessment involves comparing test valves to reference valves based on observed damage and its severity, using specific pass/fail criteria The failure modes to be evaluated and the corresponding pass/fail thresholds should be established through a thorough risk assessment This ensures a comprehensive evaluation of valve performance and longevity in accordance with industry standards.
Additional guidelines for durability testing are given in Annex M
An assessment of the fatigue performance of heart valve substitute structural components is essential to ensure durability The lifetime of each component should be determined based on the minimum duration it can withstand the expected repeated loadings encountered under in vivo conditions This evaluation guarantees the reliability and safety of the heart valve during long-term use.
The manufacturer must select and justify the appropriate fatigue assessment approach and characterization technique to accurately determine the structural lifetime of the specific material and valve or component design Proper justification ensures a reliable evaluation of durability, which is essential for safety and performance Adopting suitable methods aligns with industry standards and optimizes the evaluation of material fatigue behavior This approach helps in predicting the valve or component’s lifespan, ensuring durability and compliance with safety regulations.
Suggested guidelines are provided in Annex O `,,,```-`-`,,`,,`,`,,` -
To accurately assess structural failure modes unrelated to durability or component fatigue, specialized testing is essential For example, tests focused on stent creep can directly influence the understanding of a component or valve's overall structural lifespan Such design-specific evaluations are crucial for predicting long-term performance and ensuring reliable operation.
Examples of such design specific tests are provided in Annex N.
Preclinical in vivo evaluation
Overall requirements
An appropriate preclinical in vivo test programme shall be formulated in order to address relevant valve characteristics specific to the test heart valve substitute
The preclinical in vivo evaluation of the heart valve substitute should accurately reflect its haemodynamic performance as observed in vitro, ensuring consistent and reliable results It must also assess the surgical handling characteristics of the test valve and its accessories to confirm ease of implantation and functionality Additionally, the evaluation should provide comprehensive data on the biological reaction to the device, considering factors such as tissue response and potential for adverse reactions Relevant considerations may include, but are not limited to, these key aspects, tailored to the specific type of heart valve substitute being tested.
1) healing characteristics (pannus formation, tissue overgrowth);
5) foreign body reaction (inflammation, rejection);
7) acoustic characteristics (rigid valves), if manufacturer claims are made on this issue;
8) structural deterioration and/or non-structural dysfunction;
9) cavitation; d) use a test heart valve substitute of clinical quality; e) investigate test heart valve substitute in all positions for which it is intended (aortic, mitral, etc.); f) subject equally sized control heart valve substitutes to identical test conditions as the test heart valve substitute; g) use the same surgical techniques for the implantation of both the test and the control heart valve substitutes (e.g suture technique and orientation); h) be performed by appropriately experienced and knowledgeable test laboratories; i) address animal welfare in accordance with the principles given in ISO 10993-2
Minor design modifications to well-established heart valve prostheses can potentially eliminate the need for additional animal testing, provided that the preclinical outcomes from previous animal studies remain applicable These changes must be carefully assessed to ensure their transferability, allowing for streamlined development while maintaining clinical safety and efficacy Proper documentation and validation of previous preclinical results are essential to support this approach, ensuring regulatory compliance and patient safety.
Methods
Annex G provides guidance on conducting in vivo preclinical evaluations and outlines a series of tests to address relevant issues It emphasizes that complications following valve implantation may result from the implanted valve, the implantation environment, or their interaction Therefore, careful analysis and interpretation of post-implantation complications are essential to determine whether they are attributable to the valve, the animal, or a combination of both.
Implant animals should be of the same species, preferably matching in gender and age, to ensure consistent testing conditions The evaluated heart valve substitutes must undergo long-term testing across all anatomical positions intended for clinical use, ensuring durability and performance Animals that develop endocarditis related to the heart valve substitute may be excluded from the study; however, any cases of endocarditis must be thoroughly documented and reported to maintain transparency and data integrity.
The number of animals used for implantation of test and control heart valve substitutes shall be justified fully for each test based on the risk analysis
For long-term studies, the observation period for animals must be clearly defined based on the specific parameters being investigated, ensuring the duration is appropriate to generate meaningful data Each study protocol should provide a justified rationale for the chosen observation timeframe, which should not be shorter than 90 days to ensure sufficient data collection and reliability in results.
Each long-term animal study involving heart valve implants requires comprehensive macroscopic and histological post-mortem examinations These assessments ensure that data are collected from all animals enrolled in the study, providing thorough insights into the biocompatibility and performance of the heart valve substitute over time.
If serial blood analysis is performed, sampling shall be made pre-operatively then one week postoperatively then at appropriate intervals during the observation period as well as at termination
The assessment must identify any macroscopically visible pathological effects, such as thromboembolic events, pannus formation, or inflammatory responses around the heart valve substitute and major organs It should also evaluate structural changes in the valve, including cavitation, damage, degeneration, deformation, or calcification, both macroscopically and microscopically Additionally, a histological analysis is required to examine thromboembolic material, inflammatory reactions, and degenerative processes associated with the heart valve substitute.
Test report
The test laboratory must prepare a comprehensive test report that summarizes the data collected during the investigation, including all results from preclinical in vivo evaluations and tests outlined in Annex G The report should incorporate the complete study protocol and provide a thorough assessment of the findings Ensuring all generated data are included, the test report serves as a key document for evaluating the study’s outcomes and supporting regulatory compliance.
The test report shall include: a) identification of each of the valves used for implantation (product, serial number and other appropriate valve identification);
This article emphasizes the importance of providing a detailed description of the animal model used, including the rationale for its selection and pretest health assessments with documentation of the animal's gender, age, and any medications administered It outlines the necessity of describing the operative procedure, such as suture techniques, valve orientation, position, and any operative complications encountered Additionally, it highlights the need to document the preoperative and postoperative courses, including clinical observations, medications administered, and data from anticoagulation monitoring like INR if applicable The article also calls for reporting any deviations or amendments to the original protocol, along with detailed information about the investigators, their institutions, and the surgical team's experience with heart valve implantation and animal handling Finally, it stresses the importance of interpreting the collected data and providing recommendations regarding the clinical safety and performance of the tested heart valve substitute.
Further details of the test report depend on the defined test protocol
Guidance on the composition of the test report is given in Annex G.
Clinical investigation
Principle
Data on the safety and performance of a heart valve substitute under normal use conditions in humans are thoroughly documented, including potential side effects and associated risks The clinical investigation involves comprehensive pre-operative, peri-operative, and follow-up data collection from a specified patient cohort, with each patient having a minimum of one-year follow-up This evidence provides the necessary statistical justification for the market release of the heart valve substitute, ensuring its efficacy and safety.
General
For new heart valve designs, a clinical investigation must be conducted following this International Standard to ensure safety and efficacy When modifying an existing valve, a clinical investigation should be considered based on a thorough risk analysis of the proposed changes All clinical investigations must adhere to the guidelines outlined in ISO 14155-1 to maintain consistent quality and compliance.
Number of institutions
The clinical investigation must be conducted across at least eight institutions to ensure comprehensive data collection Each participating center is expected to implant a minimum of 15 heart valves of each type, such as aortic or mitral, to achieve statistically meaningful results This study design aims to standardize procedures and enhance the reliability of the findings related to heart valve performance Conducting the trial across multiple institutions with predefined implantation targets helps ensure robust and generalizable outcomes in heart valve evaluation.
Number of patients
A minimum number of 150 recipients of isolated aortic heart valve substitutes and a minimum number of
A minimum of 150 recipients of isolated mitral heart valve substitutes must be evaluated to ensure comprehensive safety and effectiveness data If the valve is intended for implantation in a specific position, at least 150 devices for that position should be assessed For robust statistical analysis, there should be at least 15 implants for each valve size and type, such as aortic or mitral, ensuring diverse data coverage Exceptions to this requirement include a minimum of 8 implants for aortic sizes 19 or smaller and 29 or larger, as well as mitral sizes 23 or smaller and 33 or larger, to account for limited device availability or clinical considerations.
The inclusion and exclusion criteria for patient selection shall be clearly established
NOTE All valve sizes refer to TAD in millimetres
Duration of the study
The clinical investigation must be ongoing until each valve type has been followed for at least one year in a minimum number of recipients, totaling at least 400 valve-years of follow-up per valve type (e.g., aortic or mitral) All implant data should be included in the analysis, regardless of patient outcomes within the first year or enrollment volume at participating centers.
A long-term follow-up study, in addition to the mandatory one-year patient follow-up, will be conducted based on specific principles The long-term cohort will consist of a statistically justified subset of at least 150 patients from the original group, carefully selected to minimize bias The duration of this follow-up will vary depending on the risk profile of the device design or modification, with historical data indicating a five-year follow-up for rigid heart valve substitutes and a minimum of ten years for flexible heart valve substitutes The exact length of the follow-up period will be tailored according to comprehensive risk assessment.
Clinical data requirements
Clinical data from sections 7.4.6.2 to 7.4.6.5 must be reported for all patients receiving heart valve substitutes at the specified institutions outlined in section 7.4.3 To ensure consistency, the clinical study protocol should be identical across all participating sites, except where national regulatory requirements necessitate specific protocol differences.
All valve-related complications must be reported to the principal investigator immediately Adverse events should be documented promptly and in accordance with national regulations and protocol reporting requirements Ensuring timely reporting of clinical data and adverse events is essential for patient safety and regulatory compliance.
The clinical study must incorporate suitable controls, such as historical or literature controls, involving comparable heart valve substitutes in the same position When utilizing literature data, it should originate from peer-reviewed studies published within the past five years This approach ensures the reliability and relevance of the comparative data used in the study.
The following data shall be collected: a) patient's gender and date of birth; b) investigator's name; c) name of institution
Pre-operative assessment should include collecting critical data such as the patient's diagnosis, including specific valvular lesions and their etiology, as well as any co-existing cardiovascular conditions like congestive heart failure, cardiomyopathy, peripheral vascular disease, coronary artery disease, or history of myocardial infarction Additionally, information about previous peripheral vascular surgeries and the patient's cardiac rhythm is essential for comprehensive pre-operative planning.
The assessment of a patient's cardiovascular status includes evaluating their New York Heart Association (NYHA) functional class, previous cardiovascular surgeries such as coronary artery bypass, angioplasty, valvuloplasty, annuloplasty, or heart valve replacement, and any other co-existing medical conditions like liver, kidney, or lung disease, substance abuse, diabetes, hypertension, or history of endocarditis Additionally, echocardiographic data and blood studies, including coagulation profiles with prothrombin time, partial thromboplastin time, and INR, are essential Lastly, recording physical measurements such as weight, height, and body surface area provides comprehensive health information crucial for treatment planning.
The collected data includes detailed information about the patient's heart valve surgery, such as diagnosis, procedures performed (including any concomitant surgeries), and the date of operation Essential implant details encompass heart valve substitute type, model, valve size (TAD), and serial number, along with the tissue annulus diameter (TAD) of the patient Surgical specifics also cover the chosen suture technique, retention of native valve structures, and the implant position (e.g., aortic or mitral) with relation to the tissue annulus (e.g., supra-annular, intra-annular) Additionally, the orientation of the valve disc or leaflets, complications encountered—including operative mortality and subsequent procedures—and echocardiographic evaluation within 30 days are thoroughly documented.
Follow-up data should be collected within 30 days, between 3 and 6 months after heart valve substitute implantation, then annually up to one year and onwards, until the investigation is complete Echocardiography is mandatory at all follow-up assessments to monitor valve function, unless a risk analysis determines that less frequent testing is appropriate for the patient's safety.
NOTE Additional follow-up intervals may be appropriate to documenting early or long term structural valve deterioration or non-structural dysfunction
The following data shall be collected: a) date and method of follow-up (e.g office, clinic or hospital); b) New York Heart Association functional class;
Hemodynamic evaluation by Doppler echocardiography is essential for monitoring valve performance, complemented by comprehensive blood studies including coagulation profile, hemolysis tests, and blood counts to assess patient status Follow-up visits should record the status of anticoagulant and antiplatelet therapy, while vigilant monitoring for complications such as thromboembolism, thrombosis, prosthetic valve endocarditis, structural deterioration, and reoperation is crucial Diagnostic reports—including electrocardiograms, chest X-rays, cardiac catheterization, and MRI—aid in comprehensive assessment, alongside continuous evaluation of cardiac rhythm When available, explant analysis of the test heart valve, including functional, X-ray, and histopathological investigations, provides valuable insights, with protocols for returning these valves to manufacturers or labs Documentation of death, including cause and autopsy reports, ensures thorough post-procedure evaluation.
Clinical investigation report
The report will compile comprehensive data including investigator names and institutions, patient demographics such as age and gender, and a comparison of pre-operative and post-operative NYHA functional classes It will also detail pre-operative diagnoses of valvular and co-existing diseases, operative procedures performed—including suture techniques, valve positioning relative to the tissue annulus, and leaflet orientation—along with operative complications and subsequent interventions Additionally, the report will specify implant details such as type, model, size (TAD), tissue annulus diameter, effective orifice area, and implant position Follow-up duration and methods, like clinic or hospital visits, will be documented Hemodynamic evaluation results, blood study outcomes, and therapy data will be included, referencing sections 7.4.6.3, 7.4.6.5, and related subsections The analysis of complications, re-operation reports, explant investigations, causes and dates of death, and autopsy findings will also be summarized to provide a thorough overview of the outcomes.
Pooling data from the aortic and mitral positions is justified because short-term morbidity rates are generally similar across implant sites, except for the potential risk of early valve thrombosis in the mitral position Results should be presented for the entire population and stratified by implant position and valve size (TAD) to provide comprehensive and precise insights.
This article emphasizes the importance of adhering to the 1996 Guidelines for reporting morbidity and mortality after cardiac valvular operations, including detailed analysis of causes of death and complications using appropriate statistical methods Early complication rates should be calculated as a percentage of patients for events occurring within the first 30 days and up to one year post-operation Late complications, defined as those occurring on or after the 31st day post-implant, should be assessed using linearized rates and other suitable statistical models Additionally, survival and freedom-from-complication rates should be analyzed using both actuarial (Kaplan-Meier) and cumulative incidence methods to provide comprehensive outcome assessments.
NOTE Standard errors should be reported using Greenwood’s algorithm See Andersen et al [1] d) Specific analyses shall include:
2) survival without valve-related complications;
3) freedom from specific complications, including but not limited to valve thrombosis, systemic embolism, anticoagulant-related haemorrhage, prosthetic valve endocarditis, structural deterioration of the heart valve substitute, non-structural dysfunction of the heart valve substitute, paravalvular leak, haemolysis and re-operation e) The specific complications and deaths shall be stratified as follows:
1) all complications shall be stratified by valve position and size (TAD);
2) thromboembolism shall be stratified by anticoagulation therapy and cardiac rhythm;
3) non-structural dysfunction and structural valve deterioration shall be stratified by nature of dysfunction (e.g thromboembolism, thrombosis, anticoagulant-related haemorrhage, prosthetic valve endocarditis, structural deterioration, non-structural dysfunction, paravalvular leak, haemolysis, and re-operation) Re-operation, explant and any valve-related complication shall be stratified by fatal versus non-fatal events
The data shall be analysed to determine any effect of valve tissue annulus diameter on complication rates
Clinical evaluation of a heart valve substitute post-implantation involves documenting specific complications, as outlined in section 7.4.7.2 The new or modified heart valve must demonstrate performance equal to or better than the complication rates specified in Tables R.1 and R.2 For rigorous assessment, established methods for statistical analysis of clinical data are provided in Annex R.
informative) Description of the heart valve substitute
Rationale for the provisions of this International Standard
A.1 Rationale for risk-based approach
This International Standard is built on the principle of risk management because the traditional requirements-based approach cannot keep pace with rapid technological innovation Unlike the requirements-based model, which diverts manufacturers' focus toward compliance, the risk-based approach encourages continuous evaluation of both known and potential risks associated with medical devices It prompts manufacturers to develop effective risk reduction strategies and utilize appropriate testing and analysis methods to demonstrate safety, fostering innovation and the development of inherently safer products.
This International Standard integrates a risk-based approach with best practice verification methods for evaluating heart valve substitutes It emphasizes identifying hazards and failure modes to determine necessary testing and analysis to assess associated risks The risk management process includes brainstorming, decision-making, and documentation, enabling manufacturers to evaluate, adopt, deviate from, or justify alternative methods outlined in the standard All decisions and rationales must be documented in the risk management file in accordance with ISO 14971, ensuring a thorough and compliant evaluation process.
A risk-based model emphasizes the importance of collaboration between device manufacturers and regulatory bodies responsible for verifying safety and performance compliance Manufacturers should focus on continuous improvement in device design and testing methods to enhance safety and effectiveness This approach aims to reduce reliance on extensive patient experience, ensuring that devices are validated through robust testing and innovative design.
A.2 Rationale for material, component and valve assembly testing
Assessing the stability of materials is essential for ensuring the long-term reliability and performance of heart valve substitutes International standards outline a series of performance tests that provide both quantitative and qualitative indicators of material and component stability These tests include durability and fracture mechanics assessments to estimate component lifetime, as well as evaluations of functional and safety aspects to identify potential failure modes It is the manufacturer's responsibility to conduct comprehensive testing to verify the safety and durability of heart valve implants, ensuring they meet established standards for patient safety and device longevity.
A.3 Rationale for preclinical in vivo evaluation
Preclinical in vivo evaluation aims to assess the performance of heart valve substitutes within a biological environment that closely mimics human conditions The primary goal is to ensure that the valve functions effectively and reliably before clinical application This process helps identify potential issues and verifies the safety and durability of the valve in a setting representative of human physiology.
Preclinical in vivo evaluation is the final step before human implantation, providing regulatory authorities with the necessary assurance that the test heart valve substitute will perform at least as effectively as existing clinical heart valve substitutes This stage is crucial to ensure safety and efficacy prior to approval for human use.
Currently, no single animal model is universally accepted for heart valve testing, making it essential to justify the chosen model to ensure conditions closely resemble human physiology The selected animal model must be relevant to the specific issues being investigated to produce meaningful results Since chronic studies aim to understand biological reactions to heart valve substitutes in their intended anatomical positions, long-term testing across all relevant positions is necessary for comprehensive evaluation.
Concurrent implantation of control heart valve substitutes allows for a direct comparison, serving as a benchmark for clinical performance This approach facilitates the differentiation of complications associated with the control valve versus those linked to the test valve Such comparisons enhance the accuracy of evaluating new heart valve substitutes in clinical assessments.
Verification testing for medical device compliance includes materials testing, preclinical bench testing, in vivo evaluation, and clinical investigations While clinical investigations are often part of design validation, some requirements may only be verifiable under real clinical conditions The specified tests do not constitute a complete testing program; a comprehensive approach is outlined in the risk assessment activities for heart valve substitutes Manufacturers must justify any alternative tests or modifications to testing methods, demonstrating their equivalence or superiority based on thorough risk assessments to ensure safety and efficacy.
The manufacturer conducts comprehensive validation of the heart valve substitute, including its design, packaging, labeling, and accessories Design validation for a new heart valve typically occurs in two phases: initially reviewing verification test results, manufacturing process validation, and supporting scientific and clinical evidence to ensure safety and suitability for human use The second phase aligns with the end of the clinical investigation, where data from pre-marketing approval is assessed to confirm that the device and its components are safe and ready for market approval All validation activities are thoroughly documented to demonstrate compliance and safety for market deployment.
When modifying an existing heart valve substitute design or manufacturing process, verification and validation remain essential but may have a limited scope The extent of verification and validation activities should be determined based on comprehensive risk analysis to ensure patient safety and device efficacy.
Using clinical-grade materials and components instead of generic test samples is crucial, as fillers, additives, and processing aids significantly impact material properties It's essential to design testing procedures that focus on bonded areas, such as welded, sutured, or glued joints, since these are critical points with higher potential for failure, ensuring reliable performance and safety.
A.5 Rationale for Doppler echocardiographic assessment
Two-dimensional echocardiography and Doppler echocardiography are essential, practical tools for assessing human cardiac function and heart valve substitutes The accuracy of these methods depends heavily on the skill of the operator, highlighting the importance of standardized training To ensure reliable and consistent results, it is recommended that all clinical evaluation centers follow a unified echocardiographic protocol when investigating heart valve substitutes.
A.6 Rationale for clinical evaluation reporting
The "Guidelines for Reporting Morbidity and Mortality After Cardiac Valvular Operations" have been developed through international consensus, establishing a standardized framework for transparent and accurate reporting These guidelines have been officially accepted by the Annals of Thoracic Surgery, ensuring their widespread adoption in the medical community Adhering to these publication standards improves the quality and comparability of research related to cardiac valvular procedures Implementing these guidelines enhances the clarity and consistency of morbidity and mortality data, ultimately advancing patient care and surgical outcomes.
These guidelines, published in leading journals such as the European Journal of Cardiothoracic Surgery and the Journal of Cardiovascular and Thoracic Surgery, aim to standardize the analysis and reporting of cardiac valve surgery outcomes They facilitate comparisons across different surgeons, techniques, and materials by providing clear definitions and recommendations A heart valve substitute under clinical evaluation should perform as intended, with complication rates aligning with broadly accepted performance criteria based on published follow-up data To ensure accurate risk assessment, comprehensive pre-operative, peri-operative, and follow-up data should be systematically collected, analyzed, and reported.