medical and technological achievements …...throughout the world. in 2007 the valve was registered...

MEDICAL AND TECHNOLOGICAL ACHIEVEMENTS THAT WERE REALIZED IN

THE PROSTHETIC HEART VALVE "CARDIAMED"

Introduction

The development of the valve which had been a prototype for the Cardiamed valve started in

1983. The objective of this development was to design a prosthesis that would be free from the

shortcomings intrinsic to the valves like St. Jude Medical prosthesis.

Modeling and valve design studies in order to ensure optimal hydrodynamic characteristics of

the valve had been carried out in 1983-1986.

The first clinical applications of the valve named “Carbonix-1” were started in the USSR in

1988. Since 1990 till 1994 the valve had been sold throughout the world under the trademark “Jyros”.

In 1993 the developers of the Carbonix-1 valve started their own enterprise and began to work

on the improvements for Jyros design. Only the idea of the Jyros valve, the free rotation of the leaflets

around the central axis of valve housing, was kept intact in the new valve named “MedEng”. Material,

geometry of valve leaflets, housing, and sewing cuff were modernized. A wide clinical investigation of

the valve involving about 2000 implants in 30 cardiac centres of Russia was conducted in the period

from 1994 till 1998. The results of the investigation were mainly positive but there was a need for

further improvements to increase reliability of the valve size 29-31, protect prosthesis from pannus

overgrowth, and create prostheses for the patients with narrow aortic root.

Series production and wide clinical application of the valve under the trademark “MedEng-2”

have started since 1998. More than 10000 prostheses in 80 Russian cardiac centres have been

implanted before 2003. The MedEng-2 valve has become the most common prosthesis that is used

nowadays for heart valve replacements in Russia. Many investigators from tens of cardiac centres

investigated the results of clinical application of these prostheses. More than 50 investigational results

were published and reported at scientific conferences. The overall conclusion of the investigators is that

the MedEng-2 valves are reliable, they successfully correct patient hemodynamics, the number of

specific complications, such as thromboses and thromboembolism, is minimal, hemolysis is absent

(Table 1).

2

Table 1

Authors’ conclusions Centre for cardiac surgery

Reference number of publication

According to our data derived from long-term follow-up the most

favorable data (survival, size of the left ventricle, value of diastolic

gradient) was obtained from the group of patients who received

prosthetic heart valves “MedEng”.

The Research Centre for Surgery named after А.N.

Syzganov, Almaty, Kazakhstan.

http://surgery.med.kz

Experience with more than 800 “MedEng-2”

implants

[7],[12],[26],[31]

The Russian bileaflet prostheses "MedEng-2" meets the reqirements

demanded from modern heart valve prostheses. As for hemodynamic

characteristics and the incidence of valve-related complications there

are no differences between MedEng-2 prosthesis and foreign

prostheses of similar design. On the whole the Russian MedEng-2

prostheses size 21 mm demonstrate hemodynamic performance at rest

similar to that of one of the best modern bileaflet prosthesis (St. Jude

Medical)known for aortic valve prostheses in patients with narrow

tissue annulus.

The Research Centre for Cardiovascular Surgery

named after Bakulev, Russian Academy of Medical

Sciences, Moscow.

http://www.bakulev.ru


implants

[10],[15], [24],[27],[32],[41],[43],[44]

The investigations performed had demonstrated that MedEng-2

prosthesis adequately corrects aortic and mitral heart defects and is

distinguished by good hemodynamic characteristics. The prosthesis

adequately corrects hemodynamics, is reliable and no worse than

foreign prostheses of similar design. The incidence of specific valve-

related complications is comparable with that intrinsic to valve

models of similar design manufactured abroad.

Nizhegorodskaya State Medical Academy, the

Regional Specialized Clinical Hospital for Cardiac

Surgery (Nizhegorodsky Cardiocentre), Nizhny

Novgorod.

[email protected], [email protected]


implants

[11],[13],[25],[30]

The long-term results received testify to high effectiveness and safety

of MedEng-2 prostheses in the treatment of various heart defects as

well as to their hemodynamic adequacy.

Samarsky regional clinical cardiologic dispanser,

Samara.

[email protected]


implants, [14]

3

The MedEng valves have good hemodynamic characteristics and low

percentage of complications during long-term follow-up.

The new domestic valved conduit (MedEng-2 prosthesis with the

attached vascular prosthesis) meets all the requirements of current

cardiac surgery and judging by its major clinical and instumental

characteristics is very close to the best analogous devices of foreign

production.

The Research Institute for Pathology of Blood

Circulation named after academician Е.N.Meshalkin,

Novosibirsk.

http://www.meshalkin.ru

Experience with more than 1200 "MedEng-2"

implants

[18], [19], [22],[45]

Clinical complication and mortality rates of prosthetic heart valve

"MedEng-2" are similar to those of other bileaflet cardiac prostheses

currently in use or even better. The main advantage of MedEng-2

prostheses is their safety certified by low mortality and complication

rates, and the absence of structural deterioration.

The Research Institute for Transplantology and

Artificial Organs, Moscow.

http://www.transpl.webworker.ru


implants

[28], [53],[54]

The results received give ground to believe that MedEng prosthesis at

present time is an optimal model for application in the surgery of the

acquired heart defects.

The Centre for Cardiovascular Surgery МGТS,

Faculty of Hospital Surgery of the Russian

University of Friendship among Peoples, Moscow.


implants

[34],[36]

Our observations demonstrate that the bileaflet MedEng prostheses

have good hemodynamics and high reliability.

The Regional Cardiologic Dispanser – Centre for

Diagnostics and Cardiovascular Surgery, Surgut.

http://www.okd.ru


implants

[46][16]

The use of MedEng-2 shows high survival rates and low incidence of

specific complication. Clinically the prosthesis is no worse than

foreign valve models of similar design.

Penzensky Centre for Cardiovascular Surgery,

Penza.

Experience with 75 “MedEng-2” implants

[20]

Adaptation of the MedEng-2 valve to the world market started in 2003. Special investigations

according to the requirements of the international standards and the Directive 93/42/EЕС were carried

out. Wide clinical use of the valve continues both in Russia and the countries of the former USSR

(Fig. 1). Up to 2008 more than 20.000 prostheses have been implanted. It accounts for more than 60%

of all types of the heart valve prostheses that were implanted in Russia.

4

Fig. 1 – Medeng-2 Prosthetic Heart Valve market

A special retrospective clinical investigation in accordance with the European requirements was

conducted in 2006-2007 under the supervision of German auditor. The results of this investigation have

confirmed that the valves are safe, reliable and the number of specific valve-related complications is

less than that for the other heart valve prostheses which are being used for heart valve replacements

throughout the world.

In 2007 the valve was registered in Europe and its production was transferred to the Dutch

company Cardiamed B.V. that releases it under the trademark “Сardiamed”. The valve is CE-marked.

(Annex A).

Materials

The housing and leaflets of the Cardiamed valve are made from solid isotropic pyrolytic carbon.

Technology for material production was significantly improved if compared with the technology used

for the Jyros valve. The main difference of this material from similar isotropic pyrolytic carbon used

in the St. Jude, Carbomedics, ATS, Bicarbon, On-X etc is its solidity and integrity. The leaflets of the

mentioned heart valve prostheses are made from soft graphite coated with a thin layer (about 200

microns) of durable biocompatible isotropic pyrolytic carbon (Fig. 2). Due to uniqueness of the

technology for production of the solid pyrolytic carbon, which is unavailable to the other current world

5

manufacturers of heart valve prostheses, the material has unique properties with respect to its strength

and reliability (Fig. 3).

Fig. 2 – Structure of Pyrolite® Pyrolytic Carbon

(the picture is taken from the St. Jude Medical Pyrolytic Carbon Study brochure)

Fig. 3 – Solid Pyrolitic Carbon

Comparison of the main characteristics for both types of material used for heart valve

applications is given below

Specific weight – both types of material have the same specific weight about 2.1 g/сm3

Hardness – both types of material have sufficient hardness above 1000 Мpa

Isotropy – both types of material are isotropic. In contrast to the coated material, the degree of

isotropy for the solid material is not just validated but is inspected for each workpiece in order to be

sure of isotropic properties of the material.

Anisotropic inclusions – Anisotropic inclusions due to fluctuations in the manufacturing

processes could occur in both types of material. Control over this phenomenon in the coated material is

done by validation process which is incapable to provide complete assurance. The absence of

anisotropic inclusions in the solid material is verified for each workpiece.

Strength – the solid material is 1.5 stronger than the coated material.

6

Internal stresses – the solid material is free from internal stresses that greatly reduce the

reliability of the coated material. The coated material is prone to catastrophic self-destruction when its

surface integrity is compromised. The solid material is free from such shortcoming.

Wear resistance – both types of material have minimum friction coefficients and the same wear

resistance. In contrast to the coated material the amount of wear is not critical for the solid material

because it will not lead to catastrophic consequences that would occur in the coated material when wear

amount become comparable with the thickness of its coating.

Fracture toughness - the coated materials have critical fracture toughness. Upon surface damage

of the coated material a microcrack of several microns occurs. Under cyclic loads this crack begins to

grow and over time this leads to fracture of the material [1]. The solid material is free from this effect.

Its fracture occurs exclusively when the applied load exceeds the strength of the material and that

makes valve behavior over long time more predictable.

Biocompatibility – both types of material have the same good biocompatibility. All types of tests

for toxicity, carcinogenicity, mutagenicity, hemocompatibility, etc were performed for both types of

material.

Thromboresistance – both types of material have the same good thromboresistance.

Radiopacity – due to inclusions of heavy metals the coated material is radiopaque. The solid

material contains no harmful impurities.

The stiffening ring fixed on the valve housing is made from high-strength titanium alloy that is

similar to the material used in other similar heart valves and is allowed for implant applications by the

international standards

The sewing cuff of the valve is made from polyester fibers. Chemical composition of the fibers is

similar to the chemical composition of the fabric used for sewing cuffs in other similar heart valves.

Warp-knitted fabric of the sewing cuff allows easy penetration of the needled surgical sutures and

quick tissue ingrowth, thus preventing formation of fistulas.

The accessories supplied with the valve i.e. holder, test-probe, and sizers are made from high

density polyethylene (HDPE). The material is non-toxic. However, when exposed to heat, for example,

during forbidden re-sterilization of the valve, the material may disintegrate and make the valve unfit for

clinical application. Radiation sterilization also can lead to disintegration of the materials used in the

valve, for example, it can badly affect the valve tag.

7

The general concept of the Сardiamed valve

The first mechanical heart valve prostheses had an occluder in the form of a freely floating ball

restricted by metal wire cage (for example, Starr-Edwards). Free blood flow around the ball provided

high thromboresistance to the valve but the cage elements created disturbances in blood flow and were

conductor for pannus overgrowth that triggered formation of thrombus on the cage and finally led to

valve thrombosis.

The occluder of the second generation of mechanical valves was in the form of freely floating

tilting disk (Bjork-Shilley). There were no problem with thrombus growth on the disk but the presence

of wire elements extending from the valve housing and holding the tilting disk also triggered pannus

overgrowth and formation of thrombus on the valve housing same as with the caged ball heart valves.

In the third generation of mechanical heart valves (St. Jude Medical, Omnisciense) designers had

abandoned the metal wire elements and valve occluder is held inside the valve housing with hinges.

Such valve design prevents fixation of occluder by pannus and formation of thrombus on the valve

housing but created new dangerous source of thrombose – hinge unit. Structure of blood flow in the

region of the hinge unit is strongly disturbed thus causing the stirring up of processes that lead to

formation of thrombus.

Therefore the main idea realized in the Cardiamed valve was a creation of the hinge mechanism

which involves the whole perimeter of the valve orifice and allows the valve leaflets not only to pivot

from the open position to the closed position but also to rotate around the central axis of the valve

housing. In such design the hinge zone that is prone to formation of thrombus changes its location

within the valve housing, thus preventing the creation in blood flow of the stable stagnation zones that

can trigger the process of thrombus formation.

The direction of rotation is synchronized with the direction of blood flow rotation in the heart

chambers.

This new innovative idea is patented in the, Europe [2], USA [3], China [4], Japan [5] and Russia

[6].

Realization of this idea provided additional advantages to the Cardiamed valve. There is no need

for a forced orientation of prosthesis after its suturing to tissue annulus. This is not only simplified the

surgical procedure itself but also prevented potential complications that might be caused by rotation of

the valve in situ that is the formation of fistulas, trauma of tissue annulus, valve breakage.

The availability of the hinge mechanism along the entire periphery of the valve orifice spread the

zone of hinge wear for many times thus reducing for many times the risk of valve failure due to hinge

wear.

8

The availability of the spread hinge mechanism permitted to combine the achievement of the

valves of the first generation – free floating of valve occluder in the blood flow, with the achievement

of the valves of the third generation – absence of the wire elements in the blood flow.

The structure of blood flow in the heart chambers is of complex nature depending on patient

posture (supine, seated, standing), heart rate, etc. The strictly oriented leaflets of the valves like St.

Jude Medical prosthesis disrupt the structure of blood flow. Leaflets of the Cardiamed valve float freely

and can change their orientation in accordance with the changing structure of blood flow.

During manufacturing each Cardiamed valve is tested in a pulse duplicator and during this test

the valve leaflets should make a full turn around the central axis of the valve after 100 - 200 cycles.

This is verified by visual observation through video camera and recorded in the manufacturing passport

of the valve (Fig. 4). The manufacturer admits that such stable rotation of the valve leaflets inside

human heart is impossible due to complex structure of the blood flow. However, inspection of all

explanted valves revealed that there were signs of the interaction of the leaflets with the entire

periphery of the housing and that means that their leaflets had rotated.

Fig. 4 – Rotation of the Cardiamed Prosthetic Heart Valve (test in-vitro)

Long term follow-up didn’t reveal any harmful or dangerous factors related to free rotation of the

valve leaflets of the Cardiamed valve.

The myth that the anti-anatomical orientation of leaflets in a mitral prosthesis leads to reduction

of pressure gradients is related to specifics of echocardiographic measurements that determine the

value of pressure gradient according to the width of blood stream behind the valve. Taking into account

that the structure of the blood flow between valve leaflets is asymmetric this leads to the erroneous

conclusion that pressure gradient depends on the orientation of leaflets (Fig. 5). Therefore the rotation

9

of leaflets does not affect the value of pressure gradient but may mislead echocardiographist who can

wrongly diagnose an increased pressure gradient across the prosthesis.

Fig. 5 – Visualization of the direct flow through the prosthetic valve in perpendicular planes

The possibility that the rotating leaflets impinge upon the inner cardiac structures is eliminated by

the design features of the valve (see below), compliance with instruction for use, and proper valve

sizing.

Design features of the Cardiamed valve

Anatomical fit

The Сardiamed valves are made with two types of sewing cuff: supra-annular and intrasupra-

annular (Fig. 6).

Fig. 6 – Mitral intrasupra-anular (left) and supra-annular (right) Cardiamed prosthetic heart valves

The range of available valve sizes is given in Table 2.

10

The actual tissue annulus diameter of the valve is a bit bigger than the tissue annulus diameter

(size) indicated on the valve label (Table 2). Therefore the special valve sizer supplied with the valve

should be used for proper valve sizing.

Table 2 – Basic dimensions of the Cardiamed prosthetic heart valve

Valve model Actual tissue

annulus diameter,

mm

Sewing cuff outer diameter,

mm

Orifice diameter,

mm

Body height,

mm

Leaflets exposure,

mm

Depth of interposition in ventricle,

mm

Depth of interposition

in aorta (atrium),

mm

Opening angle,

degrees

ADM.19-1In 19,5 23 14,59 7,5 2,9 4,0 4,7 ADM.21-1In 21,5 25 16,59 8,3 3,3 5,0 4,3 ADM.23-1In 23,3 27 18,34 9,5 3,3 3,8 5,7 ADM.25-1In 25,3 31 20,35 9,8 4,1 4,0 5,8 ADM.27-1In 27,3 33 22,10 10,5 4,3 4,0 6,0 ADM.29-1In 29,3 35,5 24,10 11,5 4,5 4,0 6,5 ADM.17-1Su 17,4 23 14,59 7,5 2,9 1,5 7,2 ADM.19-1Su 19,4 25 16,59 8,3 3,3 2,3 7,0 ADM.21-1Su 21,4 27 18,34 9,5 3,3 2,3 7,2 ADM.23-1Su 23,4 31 20,35 9,8 4,1 2,2 7,6 MDM.25-1In 25,5 34,0 20,35 9,8 4,1 3,4 4,9 MDM.27-1In 27,5 36,0 22,10 10,5 4,3 3,6 4,9 MDM.29-1In 29,5 38,0 24,10 11,5 4,5 4,8 5,0 MDM.31-1In 31,5 39,0 24,10 11,5 4,5 4,0 5,0 MDM.33-1In 33,5 41,0 24,10 11,5 4,5 4,0 5,0 MDM.25-1Su 25,2 36,5 22,10 10,5 4,3 1,5 8,5 MDM.27-1Su 27,2 38,5 24,10 11,5 4,5 1,4 9,1 MDM.29-1Su 29,5 38,5 24,10 11,5 4,5 3,1 8,4 MDM.31-1Su 31,5 40,5 24,10 11,5 4,5 3,1 8,4 MDM.33-1Su 33,5 40,5 24,10 11,5 4,5 3,1 8,4

83

The somewhat bigger actual tissue annulus diameter of the valves with intrasupra-annular sewing

cuff is due to the additional band made from polyester fabric (Fig. 6, pos. 1) around the valve housing.

This band provides a tight seal joint of the prosthesis with the tissue annulus. In addition the band

permits the surgeon to compensate tissue annulus erosion defects. The band facilitates quick tissue

ingrowth of the joint between the valve and the tissue annulus.

The presence of a similar band on the other side of the sewing cuff (Fig. 6, pos. 2) prevents the

curling of the cuff and introduction of the suture ends into the valve orifice.

11

In order to achieve different valve interposition in the atrium, ventricle, and aortic root the

location of the sewing cuff on the valve housing differs for each valve type and size (Fig. 7).

In case of valve insufficiency it is recommended to use the intrasupra-annular prostheses. It is

recommended to suture such prosthesis by passing the needle from the side of the atrium for the mitral

prostheses and from the side of the aorta for the aortic prostheses. This allows to obtain a reliable seal

joint between the valve and the tissue annulus.

In case of valve stenosis it is recommended to use the supra-annular prostheses. In this case the

orifice diameter of the valve is bigger for 2 mm if compared with the intrasupra-annular valve model of

the same size. Moreover the mitral prosthesis will be located mainly in the atrium with its leaflets at the

maximum distance from the ventricular walls. It is recommended to use П-shaped or knotted stitches

for valve suturing by passing the needle from the side of the ventricle for both aortic and mitral

prostheses.

Care should be taken to verify the location of the aortic prosthesis in order to avoid the blocking

of the low-situated coronary artery ostia by the sewing cuff of the prosthesis.

The width of the sewing cuff is adequate for passing surgical sutures through it. The passing of

the sutures too close to the valve housing is rather risky because the needle could hit the titanium

stiffening ring and it could lead to a significant difficulty in the passing of needle and suture through

the sewing cuff.

12

Fig. 7 – Types and sizes of the prosthetic heart valve Cardiamed

13

The height of the valve housing is sufficiently high. This was done purposefully in order to

improve hemodynamic characteristics of the valve, protect the rotating leaflets from the inner cardiac

structures, and protect the leaflets from pannus overgrowth. The high interposition of the mitral

prosthesis in the atrium does not disturb the blood flow because the active tissue ingrowth into the

sewing cuff within several weeks removes all irregularities created by the prosthesis.

It is not recommended to use the prostheses with a bigger tissue annulus diameter. If the sizer

stretches the annulus too hard, it is better to use the prosthesis of a smaller size. In particular this

concerns heart valve replacements of the mitral valves in case of their insufficiency and choice of the

valve sizes 29-33. The orifice diameters and pressure gradients respectively are absolutely the same in

the prostheses of sizes 29-33. But after mitral valve replacement and restoration of hemodynamics the

heart will shrink and this can have an additional effects on the prosthesis, if it was squeezed with

distortion into the tissue annulus (see surgical risks).

The additional orientation of the leaflets is not required. But it is necessary to check the function

of leaflets using the test-probes supplied with the prosthesis. Surgical sutures and the remainders of the

inner cardiac structures can get into the valve orifice and block the valve leaflets. The directions for use

of the test-probe should be strictly followed and the test-probe should be applied as it is shown in the

figures of the instruction for use. Otherwise the valve can be damaged (Fig. 8, 9)

Fig. 8 - Test-probe application for aortic Cardiamed prosthetic heart valve

14

Fig. 9 – Test-probe application for mitral Cardiamed prosthetic heart valve

The shape of the intrasupra-annular sewing cuff for the valves sizes 25-29 is universal and the

valve can be used, in exceptional cases, both for mitral and aortic valve replacement. In this case the

surgeon must carefully remove the valve from its holder (see instruction) and orient the valve properly

himself depending on the required position of implantation.

Hydrodynamic character is tics.

The use of solid pyrolytic carbon for the leaflets of the Cardiamed valve permitted, in contrast to

the other bileaflet heart valves, to design a leaflet with a complex aerodynamic shape that gives the

valve a number of fundamental advantages (Fig. 10).

Fig. 10 – Leaflet of the Cardiamed prosthetic heart valve

The leaflet surface facing the direct flow is made as a part of the cylinder surface. This permits to

increase greatly the forces that work on the leaflet during its opening. This ensures the stable opening

of the leaflet for a defined angle and eliminates the fluttering of the leaflets in their open position that is

15

intrinsic to the leaflets of the similar bileaflet valves. Furthermore the opening time of the valve is

reduced, its operating speed is increased along with its efficiency at high heart rate.

The concavity of the leaflet makes it more rigid that is particularly important for the prevention

of its prolapse in the closed position. In the similar bileaflet prostheses, the flat leaflets sag in the closed

position forming a slot in the region of their contact. A minor uncontrolled volume of blood

regurgitates through this slot. This regurgitant stream of blood creates cavitation that destructs the

formed blood elements and triggers hemolysis and thromboembolic complications. The Cardiamed

valve design is free from this shortcoming.

The leaflet surface facing the back flow is made as two crossing planes. At the valve inlet the

leaflet plane in the open position is parallel to the axis of flow thus eliminating the flow disturbances in

the region of the attachment points with the valve housing. At the valve outlet the leaflet plane is

inclined 10 degrees relative to the axis of flow thus causing some flow expansion and increasing of the

forces working on the leaflets during valve closure. This speeds up the valve closure and that is

important for an increase of its operating speed.

Due to unique complex aerodynamic shape of leaflets it was possible to get a practically ideal

laminar structure of flow through the valve (Fig. 11).

Fig. 11 – Direct flow through the Cardiamed prosthetic heart valve

At the side surfaces of the leaflets in the region of the attachment points with the valve housing

there are special clearances that allow the regurgitation of a defined volume of blood when the valve is

in the closed position (Fig. 12). The size of the clearances is such as to avoid the cavitation effect and

provide an adequate blood flow for proper washing of the hinge mechanism. Furthermore this defined

blood flow is oriented at an angle to the central axis of the valve thus creating the rotation of blood in

the heart chambers that eliminates the emergence of the stagnation zones. At the contact plane of the

leaflets there are also defined clearances that predetermine a minor back flow of blood for the washing

of the leaflet cams.

16

4 1

2 3

Fig. 12 – Special clearances at the Cardiamed prosthetic heart valve leaflets

Therefore the regurgitation across the Cardiamed valve, in contrast to the similar bileaflet valves,

is not chaotic but serves definite purposes. In the similar bileaflet valves the regurgitant flow through

the slots created due to strain of the leaflets is of chaotic nature with shear stresses that initiate trauma

of the formed blood elements (Fig. 13).

Fig. 13 – Regurgitant jets through different prosthetic heart valves

The direct flow of blood around the valve leaflets was experimentally and quantatively

investigated in order to determine the presence of separation zones, shear stresses, and possible blood

traumatizing factors. The studies of the back flow through the defined clearances of the valve were also

performed. These studies confirmed the absence of dangerous blood traumatizing factors (Fig. 14).

17

Fig. 14 – CFD modeling of the direct flow through the Cardiamed prosthetic heart valve

Strength character is tics

The strength of the Сardiamed valve is determined by the initial high strength of solid isotropic

pyrolytic carbon produced in-house and the initial geometry of all valve elements. Structural strength

of the valve was computed by computer simulation and proof-tested on hundreds of the valves.

The fracture load for the valve leaflet size 29 is 17.2 kg. For example, the same fracture load for

the leaflet of the Carbomedics valve determined by a comparison test was 11.7 kg.

The fracture load for the valve housing is more than 62.1 kg.

The values of assurance factor for the Сardiamed valve are shown in Fig. 15.

18

Fig. 15 - Values of assurance factor for the Сardiamed prosthetic heart valve

Margin of safety of the valve exceeds for 3 to 6 times the maximum physiological loads that can

emerge in the human heart.

To ensure valve strength each assembled valve is proof-tested during production by applying to it

a pressure of about 2000 mmHg that is 10 times more than the physiological blood pressure in the

human heart.

Valve durabili ty

During development and production the valves were tested many times in the accelerated cycling

tester for heart valves (Fig. 16). The valves tested were subjected to 16 x 108 cycles that corresponds to

40 years of valve performance in the human heart. The visual inspection of the valves after this test

revealed no signs of wear and the valves fully preserved their functional characteristics. This allows

forecasting durability of the valves for the whole lifespan of the patient.

19

Fig. 16 – Accelerated cycling tester for the prosthetic heart valves

The cardiac centres continuously follow up their patients who underwent heart valve

replacements. Up till now there were no reports on any reoperation related to the replacement of the

worn out valve or valve-related deaths due to wear of the prosthesis. The follow up period since the

first MedEng-2 implants is 14 years.

Valve re liabili ty

The valve reliability is assured by a large safety margin in all valve elements, design of the hinge

element that is practically without wear, stable manufacturing process, and continuous quality control

in accordance with ISO 9001 and ISO 13485.

The matching of the leaflets to the valve housing is done selectively using special computer

software that takes into account optimal correlation of 7 parameters, e.g. the correlation between the

material density and hardness of the leaflets and those of the housing or between their actual geometric

dimensions.

The continuous monitoring of the heart valve replacements with the MedEng-2 valves has been

underway since 1998. More than 30.000 prostheses have been implanted since that time. So far no

incident related to valve fracture or its structural deterioration that happened during surgery or after

valve implantation has been reported.

20

Clinical evaluation of the Cardiamed valves

Clinical evaluation of the MedEng-2 valves in Russia is an ongoing process. There are many

publications regarding various aspects of their clinical application. 68 cardiac surgeons from Russia,

Kazahstan, Tadjikistan, and Uzbekistan attended in 2003 a scientific conference that was dedicated to

5-year clinical experience with the heart valve prostheses “MedEng-2”. However all these publications

are in Russian and that restricts their distribution throughout the world.

In 2006 and again in 2007 multicentre clinical follow-up of the study patients according to the

international standards was performed under supervision of the auditor (Aix Scientifics) and the

Notified body (EUROCAT) from Germany.

7 centres participated in the investigation. 211 patients after isolated aortic valve replacement and

209 patients after isolated mitral valve replacement were followed for the period from 2003 till 2006.

Table 3 – Dis tribution of the s tudy patients by cardiac cen tre

Number of patients in cohort Number of patients examined (% from patients in cohort)

№ Name of investigator and centre

Aortic Mitral Total 29 35 64 1 R.М. Muratov, the Research Centre for Cardiovascular Surgery named after

А.N. Bakulev, Moscow (Centre 1) e-mail: [email protected]

26 (90%)

29 (83%)

55 (86%)

39 32 71 2 M.L. Semenovsky, the Research Institute for Transplantology and Artificial Organs, Moscow (Centre 2)

e-mail: [email protected] 36

(92%) 22

(69%) 58

(82%) 35 37 72 3 V.M. Nazarov, the Research Institute for Pathology of Blood Circulation

named after E. N. Meshalkin, Novosibirsk (Centre 3) e-mail: [email protected]

29 (83%)

34 (92%)

63 (88%)

23 24 47 4 M.A. Karpenko, the Research Institute for Cardiology named after V.A. Almazov, St. Petersburg (Centre 4)


(96%) 23

(96%) 45

(96%) 16 24 40 5 P.I. Orlovsky, the 1st Medical University named after I.P. Pavlov, St.

Petersburg (Centre 5) e-mail: [email protected]

16 (100%)

24 (100%)

40 (100%)

23 33 56 6 V.A. Chiginev, the Regional Specialized Hospital for Cardiac Surgery, Nizhny Novgorod (Centre 6) e-mail: [email protected]

21 (91%)

31 (94%)

52 (93%)

46 24 70 7 H.D. Kosmacheva Ph.D., M.D., the Regional clinical hospital No.4, Centre for Thoracic Surgery, 167, 1-May str., 350086, Krasnodar, Russia (Centre 7)


(85%) 23

(96%) 62

(89%) 211 209 420 Total 189

(90%) 186

(89%) 375

(89%)

Patient enrollment was performed by random method. Exclusion criteria are given in Table 4.

21

Table 4 - Exclus ion criteria fo r patient enrollment

End stage cardiac disease : patients excluded from heart transplant program or heart transplanted

Irreversible major organ failure with survival time expected of less than 1 year, i.e. no appropriate

therapy available to prevent anticipated death

Disseminated malignant legions, terminal cancer

HIV infection

Cerebro-vascular disease or neurological deterioration before valve implantation

Active endocarditis, sepsis or other active infection at time of implantation

Any previous prosthetic valve replacement

Double or triple valve replacement

Emergency cardiac surgery

The patient refused to participate in the investigation.

Patient is inaccessible for follow-up

End of investigation (patient’s selection is over)

Geographical site of patient residence and availability of telephone line connection with the

patient were criteria of preference for patient inclusion.

The generalized preoperative characteristic of the study patients compared with the statistical

data for the patients in the EU countries is given in Table 5. The data demonstrate that the study

population had more severe and advanced cardiovascular lesions.

Table 5 - Preoperative characterist ic o f the s tudy patients

Characteristic EU countries Study patients

Age 65 + 14 52.2 + 10.9

Gender 49.5%( F); 50.5%(M) 47%%(F); 53%(M)

Aortic stenosis 76% 35%

Aortic regurgitation 24% 65%

Mitral stenosis 28% 44%

Mitral regurgitation 72% 56%

22

Characteristic EU countries Study patients

Rheumatism of aortic/mitral

valve

12.8% / 33.9% 29.7% / 81.8%

Endocarditis А / М 2.9% / 2.7% 10.8% / 7.7%

Degeneration and other

pathologies А / М

84.3% / 63.4% 59.5% / 10.5%

Preoperative functional class

I class NYHA 13.9% 0.02%

II class NYHA 29.5% 7.6%

III class NYHA 43.1% 73.3%

IVclass NYHA 13.5% 19.1%

Concomitant diseases

Systemic hypertension 47.6% 34.5%

Lung disease 14.3% 36%

Diabetes 14.1% 3%

Hypercholestrolemia 39.7% 8.3%

Renal failure leading to

dialysis

0.4% 0%

Neurological disease 4.8% 2.1%

Previous MI 9.8% 2.6%

Carotid artery lesions 4.0% 4.8%

Tobacco abuse 37.2% 17.4%

Alcohol abuse - 4.3%

Ejection fraction of the left ventricle

<30% 2.6% 1.9%

30-50% 16.1% 22.1%

50-60% 25.7% 37%

>60% 55.5% 39%

23

All study patients were examined in the cardiac centres in 2006. This follow-up examination of

the study patients included echocardiographic studies, blood studies, and examination by cardiologist.

Statistical processing of the gathered data was performed by (Aike Scientifics)

The same study patients were examined again in the cardiac centres in 2007.

The data derived from these examinations, as the most objective ones, are used for presentation

of clinical characteristics of the Сardiamed valves.

Hemodynamic characteristics .

Hemodynamic characteristics of the valves are continuously checked during cardiovascular

operations in all cardiac centres. The long term investigation was conducted in order to find out how

hemodynamic parameters of the valves change over time. This investigation revealed no reliable data

on changes over time in pressure gradients and regurgitant volumes.

The transthoracic measurement (TTE) of pressure gradients and regurgitant volumes was

performed using 2D mode echocardiographic instruments of various models. Dimensions of the heart

chambers, pressure gradients, and regurgitant volumes were recorded preoperatively and

postoperatively during follow up for up to 5 years. The generalized values of peak and mean pressure

gradients across the Cardiamed prostheses are given in Tables 6 - таблиц Ошибка! Закладка не

определена..

Table 6 – Peak pressure gradient across p ros thesis in AVR (mmHg)

Pre-OP Post-OP 2006 2007 Valve size

Mean SD Mean SD Mean SD Mean SD

19 120 30 29 10 26 8 27 9

21 101 30 31 9 27 9 26 11

23 71 36 27 8 23 7 22 7

25 55 35 23 9 22 6 21 6

27 45 34 21 7 18 11 18 6

24

Table 6 – Mean pressure gradient across prosthes is in AVR (mmHg)



19 61 5 18 7 13 5 14 4

21 57 17 17 5 14 5 14 7

23 43 23 15 5 12 4 11 4

25 36 24 13 6 11 3 11 3

27 28 20 12 4 9 3 10 4

Table 7 – Peak pressure grad ien t across p ros thesis in MVR (mmHg)



25 17 7 13 4 14 3 12 4

27 19 8 12 4 13 4 12 4

29 22 9 11 4 12 3 12 4

31 18 11 11 3 11 3 12 4

Table 8 – Mean pressure gradient across prosthes is in MVR (mmHg)

Pre-OP Post-OP 2006 2007 Valve

size Mean SD Mean SD Mean SD Mean SD

25 9 5 5 2 5 1 5 2

27 11 8 5 2 5 2 4 2

29 11 6 4 2 5 2 4 2

31 12 6 5 1 5 2 5 2

Table 9 - Effec tive ori fice area in сm2

Position Aortic Mitral

Valve size 19 21 23 25 27 29 31 25 27 29 31

Orifice area,

АЕО(сm2)

1,5

1,75

2,2

2,6

3,0

3,0

3,0

2,2

2,6

3,0

3,0

25

Dynamics of change in functional NYHA class of the study patients were also recorded during

follow-up. The data received indicate to high efficacy of the surgery (Fig. 17).

Comparing of pre-operative and follow-up NYHA class (AVR)

0

20

40

60

80

100

120

140

160

180

I II III IV

NYHA class

Num

ber

of p

atie

nts

Pre-operativeFollow-up

Comparing of pre-operative and follow-up NYHA class (MVR)

0

20

40

60

80

100

120

140

160

I II III IV

NYHA class

Num

ber

of p

atie

nts

Pre-operativeFollow-up

Fig. 17 – Distribution of patients according to NYHA class

Patient survival

In total 31 death cases have been reported since the beginning of the clinical investigation till

2007. The reasons for death and death classification are given according to the “Guidelines for

Reporting Morbidity and Mortality After Cardiac Valvular Operations” (L. Henry Edmunds et al.).

Structure of mortality according to the “Guidelines for Reporting Morbidity and Mortality After

Cardiac Valvular Operations” (L. Henry Edmunds et al.) and the number of deaths within each period

of time are shown in Fig. 18.

All deaths for which causes had not been confirmed by the autopsy report were categorized as

"sudden, unexplained death" and classified as valve-related mortality. This reason was the major one

because no autopsy of the deceased patients had been performed and the relatives were unable to

provide documented diagnosis for the cause of death.

26

Ope

ratio

n

30 d

ays

Dis

char

ge

1 ye

ar a

fter

oper

atio

n

Follo

w-u

p

30-day mortality 15 (7 AVR, 8 MVR)

15 3 Early mortality 18

(8 AVR, 10 MVR)

15 3 2 First year mortality 20

(9 AVR, 11 MVR)

3 (1 AVR, 2 MVR)

2 (1 AVR, 1 MVR)

11 (5 AVR, 6 MVR)

Late mortality

16 (7 AVR, 9 MVR)

15 3 2 11 Total mortality 31

(14 AVR, 17 MVR) Note: AVR – aortic valve replacement MVR – mitral valve replacement

Fig. 18 - Structure of mortality

Distribution of late mortality by valve type and size is given Table 25

Table 10 – Late mortality ( later than 30 days afte r surgery)

Diagnosis AVR

(N=569.2) MVR

(N=572.2) Subtotal

(N=1141.4)

Valve related mortality 6 (1.05%) 7 (1.22%) 13 (1.14%) - reoperation because of prosthetic valve thrombosis 0 1 (0.17%) 1 (0.09%)

- Sudden, Unexpected, Unexplained Death 6 (1.05%) 6 (1.04%) 12 (1.05%)

Non-valve related mortality 1 (0.18%) 2 (0.35%) 3 (0.26%)

- Cardiac death 1 (0.18%) 1 (0.17%) 2 (0.18%) - acute heart failure 1 (0.18%) 1 (0.17%) 1 (0.09%)

- Non cardic death 0 1 (0.17%) 1 (0.09%) - lymphoblastomic lymphoma 0 1 (0.17%) 1 (0.09%)

Total 7 (1.23%) 9 (1.57%) 16 (1.40%) Note: The data are given as linearized ratio of the number of deaths to N, where N – the number of

patient-years in the corresponding sampling size.

Overall survival after 4 years was 92.1%±2.7%. Overall survival after 4 years excluding 30-day

mortality was 95.5%±2.1%. Actuarial curves of overall survival are shown in Figure 19.

27

Total actuarial survival

100.0%95.2% 95.2% 92.7% 92.1%

N=420 N=400 N=369 N=168 N=170%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4

Years of follow-up (N=Number of patients under risk)

Free

dom

from

mor

talit

y

Total actuarial survival excluding 30-day period events

100.0% 98.8% 98.8% 96.1% 95.5%

N=405 N=400 N=369 N=168 N=170%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Figure 19 – Overall survival

Survival in the AVR patients after 4 years was 92.6%±3.9%. Survival in the AVR patients after

4 years excluding 30-day mortality was 95.7%±3.3%. Actuarial curves of overall survival after AVR

are shown in Figure 20.

Total actuarial survival after AVR

100.0% 95.7% 95.7% 93.7% 92.6%

N=211 N=202 N=186 N=84 N=60%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Total actuarial survival after AVR excluding 30-day period events

100.0% 99.0% 99.0% 96.9% 95.7%

N=204 N=202 N=186 N=84 N=60%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Figure 20 – Overall survival after AVR

Survival in the MVR patients after 4 years was 91.6%±3.8%. Survival in the MVR patients

after 4 years excluding 30-day period events was 95.3%±3.0%. Actuarial curves of overall survival

after MVR are shown in Figure 21.

Total actuarial survival after MVR

100.0%94.7% 94.7% 91.6% 91.6%

N=209 N=198 N=183 N=84 N=110%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Total actuarial survival after MVR excluding 30-day period events

100.0% 98.5% 98.5% 95.3% 95.3%

N=201 N=198 N=183 N=84 N=110%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Figure 21 – Overall survival after MVR

28

Freedom from valve-related mortality after 4 years was 96.3%±2.1%. Freedom from valve-

related mortality after 4 years excluding 30-day mortality was 96.3%±2.1%. Actuarial curves of overall

freedom from valve-related mortality are shown in Figure 22.

Freedom from valve-related death

100.0% 99.0% 99.0% 96.9% 96.3%

N=420 N=400 N=369 N=168 N=170%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Freedom from valve-related death excluding 30-day period events

100.0% 99.0% 99.0% 96.9% 96.3%

N=405 N=400 N=369 N=168 N=170%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Figure 22 – Freedom from valve-related mortality

Freedom from valve-related mortality after 4 years in AVR was 96.2%±3.2%. Survival without

valve-related complications after 4 years in AVR excluding 30-day mortality was 96.2%±3.2%.

Actuarial curves of freedom from valve related mortality in AVR are shown in Figure 23.

Freedom from valve-related death after AVR

100.0% 99.5% 99.5% 97.4% 96.2%

N=211 N=202 N=186 N=84 N=60%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Freedom from valve-related death after AVR excluding 30-day period events

100.0% 99.5% 99.5% 97.4% 96.2%

N=204 N=202 N=186 N=84 N=60%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Figure 23 – Freedom from valve-related mortality (AVR)

Freedom from valve-related mortality after 4 years in MVR was 96.4%±2.7%. Freedom from

valve-related mortality after 4 years in MVR excluding 30-day mortality was 96.4%±2.7%. Actuarial

curves of freedom from valve-related mortality in MVR are shown in Figure 24.

29

Freedom from valve-related death after MVR

100.0% 98.5% 98.5% 96.4% 96.4%

N=201 N=198 N=183 N=84 N=110%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Freedom from valve-related death after MVR excluding 30-day period events

100.0% 98.5% 98.5% 96.4% 96.4%

N=201 N=198 N=183 N=84 N=110%10%20%30%40%50%60%70%80%90%

100%

0 1 2 3 4


Free

dom

from

mor

talit

y

Figure 24 – Freedom from valve-related mortality (MVR)

Specific valve-related complica tions

Linearized rates of complications according to the categories defined in the “Guidelines for

Reporting Morbidity and Mortality After Cardiac Valvular Operations” (L. Henry Edmunds et al.) are

given in Table 11.

30

Table 11 – Linearized rates o f complications by category

Aortic (569.2 pt-yrs)

Mitral (572.2 pt-yrs)

Complication

number % number %

Structural valve deterioration - - - - - wear - - - - - fracture - - - - - leaflet escape - - - - - rupture of sutures connecting valve

components - - - -

Nonstructural dysfunction 1 0.18% 1 0.17% - blockage by pannus, tissue or suture - - 1 0.17% - paravalvular fistula 1 0.18% - - - improper sizing - - - - - residual leak or obstruction after valve

implantation - - - -

- clinically significant hemolytic anemia - - - - Valve thrombosis - - 3 0.52% Embolism 16 2.81% 16 2.79% - transient ischemic attack 3 0.53% 3 0.52% - reversible ischemic neurological deficit 8 1.41% 5 0.87% - stroke or constant neurological deficit 2 0.35% 3 0.52% - peripheral embolic event 3 0.53% 5 0.87% Bleedings (Hemorrhages) 1 0.18% 1 0.17% - anticoagulant-related 1 0.18% 1 0.17% - non-anticoagulant-related - - - - Operated valvular endocarditis 2 0.35% - - Hemolysis - - - -

TOTAL 20 3.51% 21 3.67%

In accordance with section 7.4.7.2 of ISO 5840:2005, freedom from highlighted complications

was determined by Kaplan-Meier method. Confidence intervals (95%) were calculated using

Greenwood formula. The results are given in Table 12.

31

Table 12 – Actuarial freedom from spec ific complications

Complication 1 year 2 year 3 year 4 year

Structural valve deterioration 100% 100% 100% 100%

- wear 100% 100% 100% 100%

- fracture 100% 100% 100% 100%

- leaflet escape 100% 100% 100% 100%

- rupture of sutures connecting valve

components

100% 100% 100% 100%

Nonstructural dysfunction 100% 100% 99.7%±0.5% 99.7%±0.5%

- blockage by pannus, tissue or sutures 100% 100% 100% 100%

- paravalvular fistula 100% 100% 99.7%±0.5% 99.7%±0.5%

- improper sizing 100% 100% 100% 100%

- residual leak or obstruction after valve

implantation

100% 100% 100% 100%

- clinically significant hemolytic anemia 100% 100% 100% 100%

Valve thrombosis 99.8%±0.5% 99.8%±0.5% 99.8%±0.5% 99.2%±0.9%

Embolism 98.5%±1.2% 95.8%±2.0% 93.6%±2.4% 90.7%±3.4%

- transient ischemic attack 99.8%±0.5% 99.5%±0.7% 99.0%±1.0% 98.4%±1.5%

- reversible ischemic neurological deficit 99.3%±0.8% 98.3%±1.3% 96.6%±1.8% 96.6%±1.8%

- stroke or constant neurological deficit 100.0% 99.2%±0.8% 99.2%±0.8% 98.1%±1.8%

- peripheral embolic event 99.5%±0.7% 98.8%±1.1% 98.8%±1.1% 97.6%±2.0%

Bleedings (Hemorrhages) 100% 100% 99.7%±0.5% 99.1%±1.3%

- anticoagulant-related 100.0% 100.0% 99.7%±0.5% 99.1%±1.3%

- non-anticoagulant-related 100% 100% 100% 100%

Operated valvular endocarditis 100.0% 99.5%±0.7% 99.5%±0.7% 99.5%±0.7%

Hemolysis 100% 100% 100% 100%

Reoperations 99.8%±0.5% 99.3%±0.8% 98.7%±1.1% 98.7%±1.1%

Actuarial freedom from specific complications in AVR is given in Table 13.

32

Table 13 – Actuarial freedom from spec ific complications (AVR)



- wear 100% 100% 100% 100%

- fracture 100% 100% 100% 100%

- leaflet escape 100% 100% 100% 100%


components

100% 100% 100% 100%

Nonstructural dysfunction 100.0% 100.0% 99.5%±1.1% 99.5%±1.1%


- paravalvular fistula 100% 100% 99.5%±1.1% 99.5%±1.1%

- improper sizing 100% 100% 100% 100%


implantation

100% 100% 100% 100%


Valve thrombosis 100% 100% 100% 100%

Embolism 98.0%±1.9% 95.0%±3.0% 93.4%±3.5% 91.1%±4.7%

- transient ischemic attack 100% 99.5%±1.0% 98.9%±1.5% 98.9%±1.5%

- reversible ischemic neurological deficit 98.5%±1.7% 97.0%±2.4% 95.9%±2.8% 95.9%±2.8%

- stroke or constant neurological deficit 100% 99.5%±1.0% 99.5%±1.0% 98.3%±2.5%


Bleedings (Hemorrhages) 100% 100% 100% 98.8%±2.3%

- anticoagulant-related 100% 100% 100% 98.8%±2.3%


Operated valvular endocarditis 100% 99.0%±1.4% 99.0%±1.4% 99.0%±1.4%

Hemolysis 100% 100% 100% 100%

Reoperations 100% 99.5%±1.0% 99.0%±1.4% 99.0%±1.4%

Actuarial freedom from specific complications in MVR is given in Table 14

33

Table 14 – Actuarial freedom from spec ific complications (MVR)



- wear 100% 100% 100% 100%

- fracture 100% 100% 100% 100%

- leaflet escape 100% 100% 100% 100%


components

100% 100% 100% 100%

Nonstructural dysfunction 100.0% 100.0% 100% 100%


- paravalvular fistula 100% 100% 100% 100%

- improper sizing 100% 100% 100% 100%


implantation

100% 100% 100% 100%


Valve thrombosis 99.5%±1.0% 99.0%±1.4% 98.5%±1.7% 98.5%±1.7%

Embolism 99.0%±1.4% 96.5%±2.5% 93.8%±3.4% 90.3%±5.1%

- transient ischemic attack 99.5%±1.0% 99.5%±1.0% 99.0%±1.4% 97.8%±2.7%

- reversible ischemic neurological deficit 100% 99.5%±1.0% 97.3%±2.3% 97.3%±2.3%

- stroke or constant neurological deficit 100% 99.0%±1.4% 99.0%±1.4% 97.8%±2.7%


Bleedings (Hemorrhages) 100% 100% 99.5%±1.1% 99.5%±1.1%

- anticoagulant-related 100% 100% 99.5%±1.1% 99.5%±1.1%


Operated valvular endocarditis 100% 100% 100% 100%

Hemolysis 100% 100% 100% 100%

Reoperations 99.5%±1.0% 99.0%±1.4% 98.5%±1.7% 98.5%±1.7%

Anticoagulant therapy

Most patients who were examined did not maintain the INR range recommended in the

international standards. More than 60% of the patients had INR below recommended range. Due to this

34

there were practically no events of the anticoagulant-related bleedings (0,17%) in the study patients. At

the same time the incidence of thrombolic complications and thromboses corresponds with an average

world level of such complications in the patients who maintain their INR within the recommended

ranges with the incidence of anticoagulant-related bleedings equal to 4%-8%.

Distribution of the patients according to INR ranges is given in Table 15. The values are given

as percentages from the total number of the patients with the corresponding implant position. The

values for recommended ranges are highlighted by bold italic font.

Table 15 - Inte rnational Normalised Ratio (INR)

Number of patients in % from total number of AVR patients

Number of patients in % from total number of MVR patients

INR range (recommended ranges:

2.5-3.0 for AVR,

3.0-3.5 for MVR)

2006 2007 Mean value 2006 2007 Mean value

<2,0 34% 38% 36% 22% 31% 26%

2,0 – 2,4 31% 24% 27% 30% 28% 29%

2,5 – 2,9 22% 22% 22% 27% 21% 24%

3,0 – 3,5 7% 9% 8% 8% 10% 9%

3,6 – 4,0 2% 2% 2% 6% 5% 5%

>4,0 4% 6% 5% 7% 6% 6%

2.34 2.34 2.34 2.60 2.50 2.55 Mean INR

Percentage of patients with INR below norm

65% 62% 64% 79% 80% 80%

Percentage of patients with INR above norm

13% 16% 15% 14% 11% 13%

Percentage of patients with INR within recommended range

22% 22% 21% 7% 9% 7%

35

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37 17. Experience with disk prosthetic heart valves.

Belyi V.S., Polyakov V.P., Shorokhov S.Е., Goryachev V.V., Lavrov А.V., Polyakov А.V., Lyas М.N., Skuratova М.А.

Samarsky regional clinical cardiologic dispanser, Samarsky State Medical University, Samara

The 6th All-Russia congress of cardiovascular surgeons. Book of abstracts – Moscow: RC for СVS named after А.N.

Bakulev RAMS, 2000, – p. 27.

18. Application of low profile mechanical bileaflet valves “МеdEng”.

Karaskov А.М., Nazarov V.М., Semyonov I.I., Zhelezchikov V.Е., Lavinyukov S.О., Demin I.I., Kazakov А.N. The

Research Institute for pathology of blood circulation named after Е.N. Меshalkina МH RF, Novosibirsk



19. Experience with low profile bileaflet prosthesis “МеdEng”.

Nazarov V.М., Semyonov I.I., Zhelezchikov V.Е., Batalova К.S., Lavinyukov S.О., Evdokimov S.V., Melnikov E.V.

The Research Institute for pathology of blood circulation MH RF, Novosibirsk, NPP “MedEng”, Penza

20. Experience with domestic bileaflet valves “MedEng-2”.

Chagorov N.V., Pavlov А.А., Illarionov I.N., Dulatov R.М., Semyonov I.I., Nazarov V.М. Penzensky Centre for

cardivascular surgery GKB No.4, The Research Institute for pathology of blood circulation named after

academician Е.N. Meshalkin MH RF Novosibirsk



21. Experience with mitral and aortic valve replacements using prosthetic heart valves “MedEng”

Оdiyankov Е.G., Fakhreyev I.I., Petukhov V.А., Zagrebin А.L., Rykov V.V., Аnisimov S.V., Savelyev А.V. Republican

cardiologic clinical dispanser, Izhevsk



22. Experience with surgical treatment of thromboses of domestic bileaflet mechanical valves.

Каraskov А.М., Nazarov V.М., Semyonov I.I., Kuleshova R.G., Glotova N.I., Zorina I.G., Lavinyukova S.О. The

Research Institute for pathology of blood circulation named after academician Е.N. Meshalkin MH RF,

Novosibirsk



38 23. Long-term outcomes of aortic valve replacement with MedEng-2 prosthesis.

Dobrotin S.S., Zemskova Е.N., Zhurko S.А., Каlinina М.L. Nizhegorodskaya Medical Academy, the Regional Clinical

Hospital for cardiac surgery , N.Novgorod

The 10th All-Russia congress of cardiovascular surgeons. Book of abstracts – Moscow: RC for СVS named after

А.N. Bakulev RAMS, 2004, V.5, No.11. – p. 28.

24. Evaluation of immediate outcomes of mitral valve replacement with MedEng-2 prosthesis

Bokeria L.А., Skopin I.I., Tsiskaridze I.М., Izosimova М.G., Mironenko М.Yu. RC for СVS named after А.N. Bakulev

RAMS, Moscow

Current problems of cardiovascular, thoracic, and abdominal surgery. Compilation of abstracts for All-Russia

scientific & practical conference with participants from foreign countries dedicated to the 100th anniversary

birthday of Academician of RAMS F.G. Uglov / Edited by prof. V. V. Gritsenko. – StPb: StPbSMU, 2004. –

p.14-16.

25. Evaluation of the outcomes of correction of aortic stenosis using bileaflet MedEng prostheses with smal

diameter.

Dobrotin S.S., Zemskova Е.N., Каlinina М.L., Zhurko S.А. Nizhegorodskaya State Medical Academy, Specialized

clinical hospital for cardiac surgery, N.Novgorod

26. The first experience with MedEng prosthesis

Tashpulatov А.Т., Sudarikov V.F. RCS named after А.N. Syzganov, Аlmaty, Кazakhstan

27. The first experience with heart valve replacements using domestic bileaflet prostheses “MedEng-2”.

Bokeria L.А., Skopin I.I., Каramatov А.Sh., Tsiskaridze I.М., Mironenko М.Yu., Farulova I.Yu.

The Research Centre for Cardiovascular Surgery named after А.N. Bakulev RAMS, Moscow



28. The five-year experience with heart valve replacements using bileaflet MedEng-2 prostheses

Shumakov V.I., Semenovsky М.L., Vavilov P.А., Zaitseva R.S. The Research Institute for Transplantology and

Artificial Organ МH RF.


for СVS named after А.N.Bakulev RAMS, 2004. – p.62–74

29. The outcome of heart valve replacements using MedEng-2 prostheses with the sewing cuff impregnated with

heparin and antibiotics

39 Bokeria L.А., Skopin I.I., Tsiskaridze I.М., Izosimova М.G. The Research Centre for Cardiovascular Surgery named

after А.N. Bakulev RAMS, Moscow



30. The outcomes of mitral valve replacement due to rheumatic heart defects with bileaflet MedEng-2 prosthesis

Sungurovsky А.М., Frolova О.L. The Regional specialized clinical hospital for cardiac surgery, N.Novgorod

The 7th annual session of the Research Centre for Cardiovascular Surgery named after А.N. Bakulev. Book of

abstracts – Moscow: RC for CVS named after А.N. Bakulev RАМS, V.4, No.6, 2003. – p. 28.

31. Repair of left heart chambers after implantation of MedEng prosthesis into the mitral position.

Таshpulatov А.Т., Аbzaliyev К.B., Batalova К.S. The Research Cenre for Surgery named after А.N. Syzganova,

Аlmaty, Каzakhstan



32. Comparison of hemodynamic characteristic of aortic MedEng-2 and SJM prostheses, size 21, in the aortic

position.

Skopin I.I., Tsiskaridze I.М., Davydova G.B., Mironenko М.Yu., Каramatov А.Sh. RC for СVS named after А.N.

Bakulev, Moscow


for СVS named after А.N.Bakulev RAMS, 2004. – p.62–74

33. Comparison of hemodynamic characteristic of aortic MedEng-2 and SJM prostheses, size 21, in the aortic

position.

Skopin I.I., Tsiskaridze I.М., Davydova G.B., Mironenko М.Yu., Каramatov А.Sh. RC for СVS named after А.N.

Bakulev, Moscow

Current problems of cardiovascular, thoracic, and abdominal surgery. Compilation of abstracts for All-Russia

scientific & practical conference with participants from foreign countries dedicated to the 100th anniversary

birthday of Academician of RAMS F.G. Uglov / Edited by prof. V. V. Gritsenko. – StPb: StPbSMU, 2004. –

p.47-48.

34. Comparative clinical and ultrasound evaluation of implanted mechanical prosthetic heart valves ”MedEng”

and “Carbonix”.

Tarichko Yu.V, Stefanov S.А., R. Espinosa de los Monteros, Rodionova L.V. The Russian University of Friendship

among Peoples , Faculty of Hospital Surgery

40 http://www.pirogovka.ru/pdf/2004/02 hip.pdf

35. Comparative evaluation of bileaflet prostheses “ST JUDE MEDICAL” and “MedEng” in the mitral position.

Rebikov А.G., Muratov R.M., Skopin I.I., Fadeyev А.А., Babayenko S.I., Soboleva N.N., Bokeria L..А. The Research

Centre for Cardiovascular Surgery named after А.N. Bakulev RAMS, Moscow



36. Ultrasound characteristic of implanted prosthetic heart valves.

Тarichko Yu.V., Cherkasov I.Yu., Rodionova L.V. The Centre for cardiovascular surgery МGТS RF, Faculty of

Hospital Surgery of the Russian University of Friendship among Peoples кафедра госпитальной хирургии

Российского университета дружбы народов



37. Technical Conditions for MedEng-2, ТУ -9444-002-27771122-98

38. Technical Conditions for MedEng-2, ТУ 9444-006-27771122-2003

39. Long-Term Result of 1144 CarboMedics Mechanical Valve Implantations

Chang Hyun Kang, MD, Hyuk Ahn, MD, Kyung Hwan Kim, MD, and Ki-Bong Kim, MD Department of Thoracic

and Cardiovascular Surgery, Seoul National University Hospital, Seoul National University College of

Medicine, Seoul, South Korea

(Ann Thorac Surg 2005;79:1939–44)

© 2005 by The Society of Thoracic Surgeons

40. Twenty-year experience with the St Jude Medical mechanical valve prosthesis

John S. Ikonomidis, MD, PhD John M. Kratz, MD Arthur J. Crumbley III, MD Martha R. Stroud, MS Scott M.

Bradley, MD Robert M. Sade, MD Fred A. Crawford, Jr, MD

The Journal of Thoracic and Cardiovascular Surgery, Volume 126, Number 6, December 2003, р. 2022–2031.

41. Clinical and hemodynamic evaluation of modern low profile prostheses with small diameter at isolated aortic

defects in adults.

Skopin I.I., Makushin А.А., Mashina Т.V., Slivneva I.V., Karamatov А.Sh. The Research Centre for Cardiovascular

Surgery named after А.N. Bakulev RAMS, Moscow



41

42. The relationship between the effective orifice area of mitral valve prosthesis with the postoperative peak

pressure gradient.

Nemchenko Е.V., Stepanov S.S., Isakov S.V., Eliseyev L.Е., Novikov V.К. The Research Institute for Cardiology

named after V.А. Аlmazov, St. Petersburg

The Xth All-Russia congress of cardiovascular surgeons. Book of abstracts – Moscow: RC for СVS named after А.N.

Bakulev RAMS, 2005, V.6, No.5. – p. 47.

43. The immediate and intermediate outcomes of heart valve replacements with MedEng-2 prostheses.

Skopin I.I., Tsiskaridze I.М., Izosimova М.G., Mironenko М.Yu., Andreasyan S.К. The Research Centre

for Cardiovascular Surgery named after А.N. Bakulev RAMS, Moscow



44. The immediate outcomes of double valve replacements with MedEng-2 prostheses.

Skopin I.I., Tsiskaridze I.М., Izosimova М.G., Mironenko М.Yu., Andreasyan S.К.

The Research Centre for Cardiovascular Surgery named after А.N. Bakulev RAMS, Moscow



45. Experience with prosthetic heart valves “MedEng” with sewng cuff containing silver thread and antibiotics.

Karaskov А.М., Nazarov V.М., Zheleznev S.I., Lavinyukov S.О., Bogachev-Prokofyev А.V.

The Research Institute for pathology of blood circulation named after Е.N. Меshalkina МH RF, Novosibirsk



46. The outcomes of mitral and aortic heart valve replacements.

Milovanova Е.V., Uvartseva I.А., Yarkov V.I., Ulitin А.О. The regional cardiologic dispanser – The centre for

diagnostics and cardiovascular surgery, Surgut



47. The outcomes of mitral valve replacement with full or partial preservation of the valvular apparatus.

Shevchenko Yu.L., Popov L.V., Yemelyanov V.V., Volkova L.V. The National Centre for Thoracic Surgery НМХЦ

named after N.I. Pirogov МH RF, The Research Institute for Thoracic Surgery ММА named after I.М.

Sechenov

42 The 11th All-Russia congress of cardiovascular surgeons. Book of abstracts – Moscow: RC for СVS named after


48. The first results of the use of the valved conduit of domestic production for surgical treatment of aneurism of

the ascending portion of aorta.

Chernyavsky А.М., Karaskov А.М., Marchenko А.V., Alsov S.А., Kalinkina О.V., Zyryanova А.V., Evdokimov S.V..

The Research Institute for pathology of blood circulation named after academician Е.N. Meshalkin MH RF,

Novosibirsk, ZAO NPP MedEng, Penza


Bakulev RAMS, 2000, No.2. – p. 33

49. Surgical treatment of aneurism of the ascending portion of aorta with the use of the valved conduit

“МедИнж–2–VASCULAR GRAFT”

Chernyavsky А.М., Marchenko А.V., Alsov S.А., Barbukhatti К.О., Karaskov А.М., Zotov А.S.

The Research Institute for pathology of blood circulation named after academician Е.N. Meshalkin MH RF

Novosibirsk


А.N. Bakulev RAMS, 2004, V.5, No.11. – p. 56

50. The St. Jude medical cardiac valve prosthesis: a 25-year experience with single valve replacement.

R.W. Emery, MD, C.C. Krogh et.all

Cardiac surgical associates, PA, St. Paul, Minnesota

Ann. Thorac. Surg. 2005; 79: 776-83

51. Bicarbon valve - European multicenter clinical evaluation

J.B.Borman, W.G.B. Brands et all

European journal of Cardio-thoracic Surgery 13 (1998) 685-693

52. A 10-year experience with the Carbomedics cardiac prosthesis

R.Tominaga, MD, K.Kurisu, MD, et all

Ann. Thorac. Surg. 2005; 79:784-9

53. Assessment of bileaflet valves in aortic valve

P.Vavilov, V.Shumakov et all

Institute transplantology and artificial organs. Heart valve surgery

43 Abstracts / Interactive Cardiovascular and Thoracic Surgery 3 (2004) s42

54. Comparative assessment of bileaflet valves in mitral valve replacement

Shumakov V.I., Semenovsky M.L., et all

Abstracts the 14th World Congress The World Society of Cardio-Thoracic Surgeons October 14-17, 2004 p.126

55. Safety and effectiveness evaluation of the prosthetic heart valve “MEDENG-2” (“CARDIAMED”) based on

the retrospective center investigation data

Orlovsky P.I., Gritsenko V.V., Mochalov O.U., Doynikov D.N., Sharafutdinov V.E., Kuznetsov C.V., Manayenko

V.V., Kadinskaya M.I., Kuznetsov A.A., Perley V.E., Berkis V.S.

Bulletin of the RC for СVS named after А.N. Bakulev RAMS “Cardiovascular diseases”, 2007, Vol.8, №6, ISSN

1810-0694, p. 25

56. Multicenter clinical investigation of the prosthetic heart valves “MEDENG-2”

Nazarov V.M., Zheleznev S.I., Semenovskiy M.L., Zaytseva R.S., Muratov R.M., Beridze I.Z., Chiginev V.A., Zhurko

S.A., Orlovsky P.I., Doynikov D.N., Kosmacheva E.D., Tyshkevich S.N., Karpenko M.A., Suhova I.V.,

Evdokimov A.S., Evdokimov S.V.


1810-0694, p. 25

57. Comparative analysis of ECHO-CG data in 42-months post-operative period after surgical correction of the

mitral stenosis

Nikitina T.G., Osmonova A.T., Izosimova M.G., Tsiskaridze I.M., Skopin M.I., Muratov R.M., Bokeria L.A.


1810-0694, p. 41

44

Annex A –Copies of certificates

medical and technological achievements …...throughout the world. in 2007 the valve was registered...

Documents