Eur J Cardiothorac Surg 2007;32:690-695. doi:10.1016/j.ejcts.2007.08.015
Copyright © 2007, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Update of the European standards for inactive surgical implants in the area of heart valve prostheses
Walter Eichingera,*,
Sabine Däbritzb,
Rüdiger Langea
a Clinic for Thoracic and Cardiovascular Surgery, German Heart Center Munich, Lazarettstrasse 36, D-80636 Munich, Germany
b Department of Cardiac Surgery, University Hospital Grosshadern, Marchioninistrasse 15, D-81377 Munich, Germany
Received 11 April 2007;
received in revised form 10 August 2007;
accepted 15 August 2007.
* Corresponding author. Address: German Heart Center Munich, Department of Cardiovascular Surgery, Lazarettstrasse 36, D-80636 Munich, Germany. Tel.: +49 89 1218 4020; fax: +49 89 1218 4093. (Email: eichinger{at}dhm.mhn.de).
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Abstract
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Objective: The approval of a heart valve for the European market takes place in accordance with European and international standards. A new version of the EN Standards was published in June 2006, which responded to different technical innovations in the area of heart valve technology. This work outlines the differences between the new EN ISO 5840 (2005) and the old EN 12006-1 (1999). Methods: We compared the ‘new’ EN ISO 5840 (2005) and the ‘old’ EN 12006-1 (1999). Results: The following aspects have been updated in the new EN ISO 5840:- • Size designation of biological and mechanical heart valve prostheses in accordance with the patient annulus
- • Differentiation of the annular implantation position (intra-annular, intra-supra-annular, supra-annular)
- • Table for the description of the components of a heart valve prosthesis
- • Use of compliance chambers for the hydrodynamic testing of prostheses without scaffold
- • Determination of the minimum requirement for heart valve prostheses in hydrodynamic tests and specification of reference values with regard to prosthesis-related complications in clinical studies
- • Definition of the requirements for clinical long-term studies (patient number, length)
- • Introduction of an obligatory post-observation timeframe of 5 years for mechanical heart valves and of 10 years for biological heart valves.
Conclusions: The update in the new EN ISO 5840 gives consideration to the technologic evolution of heart valve development. Several changes in the new standard will improve safety for the patient and ensure high quality in the field of heart valve technology.
Abbreviations: °C = degree celsius • CEN = European Committee for Standardization • CO = cardiac output • e.g. = example given • EN = European norm • EOA = effective orifice area • ESRD = external sewing ring diameter • EU = European Union • FDA = Food and Drug Administration • IOA = internal orifice area • ISO = International Standardization Organization • kPa = kilo Pascal • min = minute • ml = milliliter • mmHg = millimeter of mercury • TAD = tissue annulus diameter • TC = Technical Committee • TÜV = Technical Inspection Association
Key Words: Heart valve prosthesis • Norm • EN • ISO
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1. Background
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The certification of marketability in the EU is issued in accordance with European law by an authorized institution, for example, in Germany by the TÜV SÜD (Southern Technical Inspection Association). The tests required for this include ‘in vitro’ as well as ‘in vivo’ studies, which are able to examine the acceptable function of the respective medical device. The approval of a heart valve for the European market takes place in accordance with European (EN) and international (ISO) standards. An amendment to the EN Standards was published in June 2006, which responded to different technical innovations in the area of heart valve technology [1]; this work outlines the differences between the new EN ISO 5840 and the old EN 12006-1 [2,3].
The new EN ISO 5840 was worked out in December 2005 by the Technical Committee ISO/TC 150 ‘Implants for surgery’ together with the Technical Committee CEN/TC 285, ‘Inactive Surgical Implants’, of the European Committee for Standardization under a mandate that the European Commission and the Free Trade Association issued to the CEN. The ‘Heart Valve Prostheses’ study group of the Standards Committee for Precision Engineering and Optics (NAFuO) in the German Institute for Standardization (DIN) agreed to the content of the EN ISO 5840. The European Standard EN ISO 5840:2005 furthermore has the status of a German standard. CEN members are the national standardization institutions of Austria, Belgium, Cyprus, Denmark, Germany, Estonia, Finland, France, Greece, Hungary, Ireland, Iceland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Slovakia, Sweden, Switzerland, Spain, the Czech Republic, and the United Kingdom [1].
As a basis for the new European EN, ISO 5840 served the American ISO/CD 5840 which is also the basis for the approval of the United States by the Food and Drug Administration (FDA) [1,2].
A critical analysis of the existing comprehensive body of regulation was already conducted in the Scientific Advisory Board of the TÜV SÜD. The EN and the ISO were compared and adapted in the sense of a simplification of the standards. The complete changes for the updating and optimization of the comprehensive body of regulations are summarized as below.
1.1 The study process for the approval of a cardiovascular implant
The new standards represent the foundation for the approval of a newly developed heart valve. They specify the exact type of tests to be conducted, the requirements for the test equipment used, and the documentation of the test results.
1.1.1 ‘In vitro’ testing
First of all, the ‘in vitro’ testing of the heart valve and its components takes place under conditions that come as close as possible to the ‘in vivo’ conditions. For example, the proper function of a heart valve is tested under normotensive, hypotensive, and different hypertensive conditions.
1.1.2 Pre-clinical ‘in vivo’ testing
The next step consists of the pre-clinical ‘in vivo’ testing on the animal model. The goal of the pre-clinical implantation in the animal is the evaluation of those performance characteristics of the heart valve that are not ascertainable by an ‘in vitro’ test. Examples of this are: thromboembolisms, hemolysis, calcification, and biocompatibility. Animal studies also provide the opportunity to evaluate specific surgical–technical peculiarities in the implantation, as well as to investigate the hemodynamic function of the prostheses under conditions that approximate human ones.
1.1.3 Clinical evaluation
After the ‘in vitro’ and ‘in vivo’ testing is successfully concluded, clinical licensing studies are required that take place in different independent clinical institutions. The first phase of the clinical study includes a small amount of patients and initially a brief period of after-care, to expose possible early problems arising from the heart valve. Studies on larger patient collectives and a longer study timeframe are then required for a detailed analysis of prosthesis-related peculiarities and complications.
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2. Valve size labeling of biological and mechanical heart valves by the manufacturer
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The classification of the size designation for heart valve prosthesis has been only insufficiently regulated in the EN until now. Since the introduction of so-called ‘intra-supra-annular’ and ‘complete supra-annular’ heart valve prostheses for the replacement of the aortic valve, the existing regulations are no longer sufficient for the identification of the prosthetic size of the EN. In recent years, this situation has led to the fact that a more reasonable, more objective comparison of different heart valve prostheses is no longer possible based on the valve size indicated by the valve manufacturer, since the actual geometric dimensions of the different prostheses can vary substantially despite the same size indication by the manufacturer [4–7].
Therefore, the EN ISO 5840:2005 standard defines that the size designation of all prostheses in aortic position is based on the so-called ‘tissue annulus diameter’ which is defined as the diameter of the smallest flow area within the aortic annulus of the patient after removal of the native valve [1].
Example: A prosthesis that can be implanted in a patient with an aortic annulus of 23 mm receives the labeled size ‘23’. From the patient's point of view, this means that a patient with an aortic annulus of 23 mm can receive a prosthesis of the size of ‘23’ regardless of the manufacturer and model. In addition, the valve size label indicated by the manufacturer must contain details on the implantation position, height, and suture technology.
Example: A heart valve prosthesis is provided for the implantation in different locations (aortic, mitral, pulmonary, tricuspid location). Specifically, the aortic valve prostheses can be implanted in different positions (intra-annular, intra-supra-annular, complete supra-annular) and with different suture techniques (everting/non-everting sutures). These different implantation conditions influence the choice of the valve size.
As depicted in Fig. 1
, the implantation of a larger prosthesis is possible through complete supra-annular positioning with the same diameter of the aortic annulus (tissue annulus diameter (TAD)) of the patient. In accordance with the suggestion of the ISO, the size designation of the smaller intra-annular and of the larger supra-annular prosthesis would be equal, since the TAD is equal. Upon comparison of the hemodynamic values such as effective orifice area or pressure gradients, as expected, the complete supra-annular prosthesis would then show more favorable results. If instead, the valve size labeling would follow the geometric prosthetic size, as most presently, the use of a larger prosthesis with equal annulus would no longer be considered.
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Fig. 1. Schematic representation of the annular position of a heart valve prosthesis.- Tissue annulus diameter: Diameter of the smallest flow area within the annulus of the patient.
- Complete supra-annular suture ring: The design of the suture ring allows a prosthetic implantation completely above the tissue annulus of the patient.
- Intra-supra-annular suture ring: The design of the suture ring allows a prosthetic position, in which a part is positioned above the tissue annulus of the patient and a part is positioned within the tissue annulus.
- Intra-annular suture ring: The design of the suture ring enables a complete prosthetic implantation, at least predominantly within the tissue annulus of the patient.
- Valve size: The manufacturer information of the measures of the heart valve prostheses, which corresponds to the tissue annulus of the patient, is provided for the prosthesis (i.e., the tissue annulus represents the designed valve size!).
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3. Functional area of the heart valve prosthesis
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The EN ISO 5840:2005 contains an overview of physical and physiological parameters for the in vitro testing. All heart valve prostheses must be designed in such a way so that they function properly in the total range of the parameters indicated. A corresponding overview was also found in written form in the EN and has been amended for a better overview in table form. Table 1
represents the adapted and more concise representation, as it was admitted into the EN ISO 5840:2005 (page 17, 6.2.1; Table 1) [1].
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4. Use of compliance chambers for the hydrodynamic testing of stentless prostheses in vitro
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The function of stentless aortic prostheses is dependent on the compliance of the vessel in which the valve is implanted. Therefore, testing in chambers with different compliance is necessary. Comparable testing of stentless mitral valve prostheses should take place in the same way (Table 2
).
The EN ISO 5840:2005 contains a new table with the minimum requirements for heart valve prosthesis within the hydrodynamic tests (Table 3
) [1].
4.1 In vitro tests of stentless heart valve prostheses in ‘compliant chambers’
When the pressure difference and/or the degree of a possible insufficiency is influenced by the compliance of the vessel in which the valve is implanted, the valve should be tested in specific chambers. A chamber with lower compliance as a model of the patients with normal aorta, a chamber with higher compliance as model for young patients and patients with hypercompliance (see Annex F of the EN ISO 5840:2005). The recommended definition of compliance is:
with C, compliance; P
1, diastolic pressure; P
2, systolic pressure; D
1, outer diameter with P
1; D
2, outer diameter with P
2.
A small (e.g., 19 mm) and a large prostheses (e.g., 31 mm) presently serve as commercial reference valves of a stentless prosthesis. For hydrodynamic testing, the test valves should be tested with stationary forward flow in the chamber with lower compliance with low, normal, and high pressure (corresponding to Table 1). The tests for the measurement of the pulsatile regurgitant fraction of stentless prostheses should be tested in both chambers under low-, normal-, and high-pressure conditions. The tests for durability should be carried out in the chamber with lower compliance [1].
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5. Comparison of the testing criteria between the ‘old’ EN 12006-1 and the ‘new’ EN ISO 5840:2005
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The following comparisons for the testing of the endurance strength in vitro, for the pre-clinical evaluation of the heart valves in vivo, and for the clinical evaluation show that the requirements in relation to these three parameters are not essentially different (Table 4
).
5.1 Designation of reference values with regard to the prosthesis-related complications in clinical studies
In the new EN ISO 5840:2005, reference values are now added in table form for prosthesis-related complications (Annex R, Tables R1 and R2), which were not listed in the old EN 12006-1 [1]. The new tables are listed in the Tables 5 and 6
.
5.2 Clinical test
The new EN ISO 5840:2005 gives consideration to the commitment to a precise documentation of the data to be ascertained from clinical long-term studies including the Kaplan–Meier analyses and the cumulative incidences of complications by extending the post-observation phase for each patient to 5 years (mechanical prosthesis) and 10 years (bioprosthesis). For the first time these timeframes are obligatory in the EN ISO 5840:2005 (neither the old EN 12006-1 nor the new ISO 5840 named a obligatory timeframe) [1–3].
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6. Summary
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The following aspects have been updated in the new EN ISO 5840 [1]:
Size designation of biological and mechanical heart valve prostheses in accordance with the patient annulus
- Differentiation of the annular implantation position (intra-annular, intra-supra-annular, supra-annular)
- Table for the description of the components of a heart valve prosthesis
- Use of compliance chambers for the hydrodynamic testing of prostheses without scaffold
- Determination of the minimum requirement for heart valve prostheses in hydrodynamic tests and specification of reference values with regard to prosthesis-related complications in clinical studies
- Definition of the requirements for clinical long-term studies (patient number, length)
- Introduction of an obligatory post-observation timeframe of 5 years for mechanical heart valves and of 10 years for biological heart valves.
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7. Conclusions
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The new EN ISO 5840:2005 updated points of major interest for the cardiac surgeon. Sizing and implantation position especially (intra-annular, intra-supra-annular, supra-annular) were not clearly defined in the past EN Standards and led to confusion when comparing valves of different manufacturers. By defining the size designation in accordance to the patient's annulus, comparisons of different valves should be possible on the basis of the labeled valve size in the future.
For centers participating in approval studies it is of importance to recognize the introduction of an obligatory post-observation timeframe for mechanical and biological heart valves.
The other changes included in the new EN 5840:2005 do not directly influence the daily practice of the cardiac surgeon, but are of major relevance for a further unification of the approval process for manufacturers.
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References
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- Cardiovascular implants – Cardiac valve prostheses. Norm EN ISO 5840:2005(E); 2005.
- Cardiovascular implants – Cardiac valve prostheses. Norm ISO/CD 5840; 2002.
- Besondere Anforderungen für Herz- und Gefäßimplantate, Teil 1: Herzklappenprothesen; Deutsche Fassung. Norm EN 12006-1:1999 Teil 1 Oktober 1999; 1999.
- Botzenhardt F, Eichinger WB, Bleiziffer S, Guenzinger R, Wagner IM, Bauernschmitt R, Lange R. Hemodynamic comparison of bioprostheses for complete supra-annular position in patients with small aortic annulus. J Am Coll Cardiol 2005;45(12):2054-2060.
- Christakis GT, Buth KJ, Goldman BS, Fremes SE, Rao V, Cohen G, Borger MA, Weisel RD. Inaccurate and misleading valve sizing: a proposed standard for valve size nomenclature. Ann Thorac Surg 1998;66(4):1198-1203.
- Eichinger WB, Botzenhardt F, Guenzinger R, Bleiziffer S, Keithahn A, Bauernschmitt R, Lange R. The effective orifice area/patient aortic annulus area ratio: a better way to compare different bioprostheses? A prospective randomized comparison of the Mosaic and Perimount bioprostheses in the aortic position. J Heart Valve Dis 2004;13(3):382-388[discussion 388–9].
- Walther T, Falk V, Weigl C, Diegeler A, Rauch T, Autschbach R, Mohr FW. Discrepancy of sizers for conventional and stentless aortic valve implants. J Heart Valve Dis 1997;6(2):145-148.
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Abstract
1. Background
