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Buněčná terapie kritické

končetinové ischemie

(NO-CLI)

Václav Procházka

Fakultní nemocnice Ostrava

Výbor pro zdravotnictví PSP ČR

Praha, 8. ledna 2015

Diskutovaná problematika

1. Je léčba kmenovými buňkami v problematice kritické končetinové ischemie

léčbou “Lege artis” ?

2. Je léčba pomocí kmenových buněk získaných z kostní dřeně “metodou

účinnou”?

3. Je léčba využívanými zdravotnickými prostředky k této léčbě “bezpečná”?

4. Je tato léčba “schválená” státními autoritami na pracovištích, která tuto léčbu

provádějí?

5. Existuje dostatečná “vědecká podpora” v klinických hodnoceních pro zařazení

kódu výkonu do sazebníku k úhradě ze zdravotního pojištění?

6. Byl postup žádosti o zařazení kódu výkonu 12520 a 12530 standardní?

7. Je snaha odborných společností o zařazení nového způsobu léčby “etická”?

Počet léčených pacientů s DM k 31. 12. daného roku

Počet lé

čených p

acie

ntů

s D

M*

0

100 000

200 000

300 000

400 000

500 000

600 000

700 000

800 000

900 000

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Zdroj: Výkazy o činnosti zdravotnických zařízení pro obor diabetologie (A04), období: 2000-2013

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Počet

pacientů654 164 653 418 667 135 686 865 712 079 739 305 748 528 754 961 773 561 783 321 806 230 825 382 841 227 837 215

* diabetes je definován jako E10, E11, E13, R73.0

Počet případů diabetické nohy a počet amputací

0

5 000

10 000

15 000

20 000

25 000

30 000

35 000

40 000

45 000

50 000

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Zdroj: Výkazy o činnosti zdravotnických zařízení pro obor diabetologie (A04), období: 2000 - 2013

Počet pří

padů

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Diabetická

noha37 764 36 725 38 166 37 971 39 753 38 090 41 328 42 337 42 992 43 990 45 118 44 011 43 248 44 657

Amputace

(%)

5 865

(15,53 %)

6 118

(16,66 %)

6 743

(17,67 %)

7 029

(18,51 %)

7 444

(18,73 %)

7 303

(19,17 %)

7 834

(18,96 %)

7 853

(18,55 %)

8 169

(19,00 %)

8 439

(19,18 %)

8 501

(18,84 %)

10 408

(23,65 %)

10 425

(24,11 %)

11 168

(25,01 %)

Diabetická noha

Amputace

Kritická končetinová ischemie

Amputace na operačním sále

Saint Thomas Hospital, London,

okolo roku 1775

Komplikovaný zdravotnický problém

FAGLIA ET AL., DIABETES CARE. 2009 MAY;32(5):822-7

Kritická Končetinová Ischemie – Prognózaa

Meta-Analysis Major Amputations and Survival

in 564 patients with CLI and diabetes

Major Amputation

CLI Diagnosis: 1.) Ankle Blood Pressure: <70 mmHg, 2.) TcPO2 < 50 mmHg

Survival

CLI Prognosis: No Revascularization Possible in 20-50%

Počet úmrtí u pacientů s DM za sledované období

Zdroj: Výkazy o činnosti zdravotnických zařízení pro obor diabetologie (A04), List o prohlídce zemřelého, období: 2000 - 2013

Počet úm

rtí

0

5 000

10 000

15 000

20 000

25 000

30 000

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Jakékoliv úmrtí u

pac. s DM (A04)22 852 23 460 23 421 24 603 23 725 23 326 23 521 22 869 22 259 21 747 22 286 23 290 23 886 25 508

DM mezi příčinami

úmrtí (LPZ)#13 037 11 983 11 470 11 436 11 269 11 154 10 759 10 990 11 061 10 821 11 502 12 369 11 915 -

Úmrtí z jakékoliv příčiny

u pacientů s DM* (dle A04)

DM* uveden mezi příčinami

úmrtí pacientů (dle LPZ)

# rok 2013 nezobrazen z důvodu nekonzistence sběru dat (v období 2000-2012 může být v datech uvedeno celkem 6 dg - 3 hlavní, 3 vedlejší, v datech za rok 2013

může být uvedeno až 40 diagnóz).

* diabetes je definován jako E10, E11, E13, R73.0

Klinické studie s buněčnou terapií pro NO-CLI 12ti leté zkušenosti

Author Year Trial

Type

N

Total

N

Treated

N

Control

Benoit (6) 2011 RCT 48 34 14

Idei (32) 2011 Cohort 97 51 46

Lu (42) 2011 RCT 82 41 41

Madaric (44) 2011 Case series 31 31 0

Murphy (51) 2011 Case series 30 30 0

Perin (55) 2011 Case series 10 10 0

Powell (56) 2011 RCT 46 32 14

Ruiz-Salmeron (58) 2011 Case series 20 20 0

Subrammaniyan (65) 2011 Case series 6 6 0

Walter (69) 2011 RCT w cross 40 19 21

Burt (8) 2010 Case series 9 9 0

Higashi (26) 2010 Case series 16 16 0

Horie (27) 2010 Case series 162 162 0

Lara-Hernandez (38) 2010 Case series 28 28 0

Mizuno (48) 2010 Case series 8 8 0

Prochazka (57) 2010 RCT 96 42 54

Amann (1) 2009 Case series 51 51 0

Franz (19) 2009 Case series 9 9 0

Kawamoto (36) 2009 Case series 17 17 0

Moriya (49) 2009 Case series 42 42 0

Chochola (9) 2008 Case series 24 24 0

Cobellis (10) 2008 Case series 10 10 0

De Vriese (11) 2008 Case series 16 16 0

Matoba (46) 2008 Case series 115 115 0

To Date: 45 Clinical Trials (7 RCT) including 1272 Patients.

Cell Transplant. 2013;22(3):545-62. Benoit E1, O'Donnell TF, Patel AN.

Author Year Trial

Type

N

Total

N

Treated

N

Control

Motukuru (50) 2008 Case series 36 36 0

Napoli (52) 2008 Cohort 36 18 18

Van Tongeren (68) 2008 Case series 27 27 0

Wester (70) 2008 Case series 8 8 0

Zhang (72) 2008 Case series 15 15 0

Bartsch (5) 2007 Cohort 25 13 12

Hernandez (24) 2007 Case series 12 12 0

Huang (31) 2007 Case series 150 150 0

Saito (60) 2007 Case series 14 14 0

Arai (2) 2006 RCT 25 13 12

Durdu (12) 2006 Case series 28 28 0

Koshikawa (37) 2006 Case series 7 7 0

Miyamoto (47) 2006 Case series 8 8 0

Huang (29) 2005 RCT 28 14 14

Ishida (33) 2005 Case series 6 6 0

Lenk (39) 2005 Case series 7 7 0

Higashi (25) 2004 Case series 7 7 0

Huang (30) 2004 Case series 5 5 0

Saigawa (59) 2004 Case series 8 8 0

Esato (14) 2002 Case series 8 8 0

Tateishi-Yuyama (66) 2002 Case series 45 45 0

Proces zpracování a aplikace kostní dřeně

Aspirate the desired volume of

Bone Marrow

Aspirate

Gradient densitycentrifuge

Process

Bone Marrow Aspirate

Concentrate [BMAC]

Utilize

15

Min.

V režimu “Point-of-Care”

10 minut 15 minut 15 minut

PŘED PO

PŘED PO

PŘED PO

PŘED PO

PŘED PO

PŘED PO

D-60

28

Požadavek Hodnota

1.1. Propouštění kmenových buněk z kostní dřeněk přímému použití

Provádí pracovník na min. úvazek 0,5 s funkcí odpovědné osoby dle zákona 296/2008 Sb.

1.2. Místo zpracování kmenových buněk z kostní dřeněurčených k léčbě kritické ischemie dolních končetinprováděné

Povinná třída čistoty zpracování buněk je tř. (B)>A na pozadí (C)>B „EMA position paper“

1.3. Technologie zpracování kostní dřeně za účelemvýroby kmenových buněk

Technologie s CE značkou dedikovanýmpoužitím k bezpečné přípravě autologního koncentrátu buněk z kostní dřeně, určených přímo k aplikaci do ischemické tkáně při léčbě kritické končetinové ischemie (vydáno EMA notified body)

1.4. Povolení k činnosti centra provádějící odběranebo zpracování kostní dřeně za účelem výrobykmenových buněk určených k léčbě kritické ischemiedolních končetin

Povolení k činnosti tkáňového zařízení dle zákona 296/2008 Sb.

1.5. Specifikace centra provádějící zpracování kostnídřeně za účelem výroby kmenových buněk určenýchk léčbě kritické ischemie dolních končetin

Typ buněk: Kmenové buňky z kostní dřeněAutologní použití,Rozsah činnosti: zpracování, vyšetřování, propuštění k přímému použití (v rámci jednoho chirurgického zákroku)

1.6. Požadavky na materiál centra provádějící odběranebo zpracování kostní dřeně za účelem výrobykmenových buněk určených k léčbě kritické ischemiedolních končetin

Výhradní použití materiálů a technologií, které disponují platnou CE značkou

Požadavky SÚKL na kvalitu a bezpečnost výroby

Řídí se zákonem 296/2008 Sb.

Typ Buněk Průměrný % zisk

buněk při

zpracování

Průměrný počet

buněk

Krevní destičky x

106 /ml

73.9 ± 17.1 794x106 ± 429

Mononukleární

elementy

70.2 ± 29.9 376 x 106 ± 79

CD34+ buňky x 106

/ml

74.6 ± 13.7 9.02 x 106 ± 4.3

CFU-

Fibroblasty/cm3

3.040 ± 1.251 60.800 ± 29.200

Buněčný

marker

Average value Standard

deviation

CD 34 [%] 0.7 ± 0.42

CD10 [%] 15 15 ± 7.07

CD 13 [%] 40 ± 0

CD 14 [%] 0 ± 0

CD 24 [%] 5 ± 7.07

CD 29 [%] 100 ± 0

CD 31 [%] 87.5 ±17.68

CD 36 [%] 25 25 ± 21.21

CD 38 [%] 77.5 ± 3.54

CD 44 [%] 90 ± 14.14

CD 49 [%] 2.5 ± 3.54

CD 73 [%] 45 ± 63.64

CD 90 [%] 7.5 ± 3.54

CD 105 [%] 92.5 ± 3.54

CD 106 [%] 10 ± 0

CD 117 [%] 75 ± 21.21

CD 133 [%] 70 ± 28.28

CD 166 [%] 70 ± 42.43

HLA-DR [%] 82 ± 7.07

HLA-ABC [%] 100 ± 0

Požadavky SÚKL na kvalitu propouštěných buněk

1.Požadavky na buněčný rozpočet koncentrátu 2.Požadavky na imunofenotypizaci koncentrátu

Požadavky na výstupní kvalitu koncentrátu

- Sterilita výsledného produktu (negativní

bakteriologické a virologické vyšetření)

- Nejméně 95% viabilita buněk s CD34+

znaky v koncentrátu

Požadavky na vyšetření dárce

- Serologické vyšetření dárců na hepatitidu,

CMV, EBV, HIV, TPPA,HSV,VZV

Prospective Non-randomized Study Autologous

Bone Marrow Stem Cell Transplantation in CLI

and Diabetic Foot

98 patients – NO-CLI and foot ulcer

Group I (BMAC) - 42 patients

(36 M, 6F mean age of 66.2±10.6)

Group II (Control) - 56 patients

(44 M, 12F mean age of 64,1±8,6)

BMAC in NO-CLI and Foot Ulcer

44%

21%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Control BMAC

Cell Transplantation , Vol. 19, pp. 1413–1424, 2010 0963-6897/10 $90.00 + .00

Printed in the USA. All rights reserved. DOI: 10.3727/096368910X514170

Copyright Ó 2010 Cognizant Comm. Corp. E-ISSN 1555-3892

www.cognizantcommunication.com

Cell Therapy, a New Standard in M anagement

of Chronic Critical L imb I schemia and Foot Ulcer

V. Prochazka,* J. Gumulec,† F. Jaluvka,‡ D. Salounova,§ T. Jonszta,* D. Czerny,*J. Krajca,* R. Urbanec,‡ P. Klement,¶ J. Martinek,# and G. L. Klement**

*Radiodiagnostic Institute, University Hospital Ostrava, Ostrava-Poruba, Czech Republic

†Hemato-Oncological Center, University Hospital Ostrava, Ostrava-Poruba, Czech Republic

‡Surgery Clinic and Anaesthesiology Department, University Hospital Ostrava, Ostrava-Poruba, Czech Republic

§Department of Mathematical Methods in Economy, VSB-Technical University Ostrava, Ostrava-Poruba, Czech Republic

¶Henderson Research Center, McMaster University, Hamilton, Ontario, Canada

#Clinical Laboratory, J.G. Mendel Cancer Center, Novy Jicin, Czech Republic

**Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical University, Boston, MA, USA

Fifty percent of diabetics (7% of general population) suffer from peripheral arterial occlusive disease, whichmay lead to amputation due to critical limb ischemia (CLI). The aim of our study was to prevent major limbamputation (MLA) in this group of patients using a local application of autologous bone marrow stem cells(ABMSC) concentrate. A total of 96 patients with CLI and foot ulcer (FU) were randomized into groups Iand II. Patients in group I (n = 42, 36 males, 6 females, 66.2 ± 10.6 years) underwent local treatment withABMSC while those in group II (n = 54, control, 42 males, 12 females, 64.1 ± 8.6 years) received standardmedical care. The frequency of major limb amputation in groups I and II was 21% and 44% within the 120days of follow up, respectively (p < 0.05). Only in salvaged limbs of group I both toe pressure and toebrachial index increased (from 22.66 ± 5.32 to 25.63 ± 4.75 mmHg and from 0.14 ± 0.03 to 0.17 ± 0.03,respectively, mean ± SEM). The CD34+ cell counts in bone marrow concentrate (BMC) decreased (correla-tion, p = 0.024) with age, even though there was no correlation between age and healing. An unexpectedfinding was made of relative, bone marrow lymphopenia in the initial bone marrow concentrates in patientswho failed ABMSC therapy (21% of MLA). This difference was statistically significant (p < 0.040). Weconclude ABMSC therapy results in 79% limb salvage in patients suffering from CLI and FU. In the remain-ing 21% lymphopenia and thrombocytopenia were identified as potential causative factors, suggesting thatat least a partial correction with platelet supplementation may be beneficial.

Key words: Critical limb ischemia (CLI); Diabetic foot ulcer; Autologous bone marrow stem cells (ABMSC);Lymphopenia of bone marrow

I NTRODUCTI ON suddenly and causes 50–67% of all nontraumatic lower

extremity amputations. Fifty-two percent of diabetics

with CLI die during the 4.5 year follow up (35,36).In diabetic patients, nonhealing cutaneous ulcers are

a significant clinical, social, and healthcare problem. Standard treatment of chronic wounds, and especially

those secondary to CLI, includes surgical revasculariza-Based on more than 10 million diabetic patients in the

US and an estimated prevalence of 15% for chronic cu- tion (distal crural or pedal bypass), endovascular therapy

(recanalization by percutaneous transluminal angioplasty),taneous ulcers, there are approximately 1.5 million pa-

tients with this problem. Peripheral arterial occlusive or maximum podiatric wound care (hyperbaric oxygen,

antibiotics, vasodilators). Despite the available thera-disease (PAOD) has been recognized as a significant

factor in this population. For example, in European pies, 25% of patients still progress to amputation. The

outcomes are even worse in diabetics, with multicausalStudy Group on Diabetes and Lower Extremity (Eurodi-

ale) 49% of patients presenting with new diabetic foot disease, where neuropathy, poor healing, and peripheral

arterial occlusive disease occur simultaneously. Thirtyulcer had PAOD. Critical limb ischemia (CLI) develops

Received February 1, 2010; final acceptance May 13, 2010. Online prepub date: June 7, 2010.Address correspondence to Vaclav Prochazka, M.D., Ph.D., M.Sc., Interventional Neuroradiology and Angiology, Radiology Department, Ave 17.Listopadu 1790, University Hospital Ostrava, Ostrava-Poruba, 70852, Czech Republic. Tel: 00420 59737 2172; Fax: 00420 59737 2175; E-mail:angio@vol.cz

1413

Amputation rate

Chin Med J 2012;125(23):4296-4300

4296

Meta analysis

Autologous bone marrow stem cell transplantation in critical limb ischemia: a meta-analysis of randomized controlled trials LIU Fu-peng, DONG Jian-jun, SUN Shu-juan, GAO Wei-yi, ZHANG Zhong-wen, ZHOU Xiao-jun, YANG Liu,

ZHAO Jun-yu, YAO Jin-ming, LIU Meng and LIAO Lin

Keywords: bone marrow-derived cells; stem cells; transplantation; critical limb ischemia; meta-analysis

Background Amputation-free survival (AFS) has been recommended as the gold standard for evaluating No-Option

Critical Limb Ischemia (NO-CLI) therapy. Early-phase clinical trials suggest that autologous bone-marrow derived cells

(BMCs) transplantation may have a positive effect on patients with NO-CLI, especially decreasing the incidence of

amputation. However, the BMCs therapeutic efficacy remains controversial and whether BMCs therapy is suitable for all

CLI patients is unclear.

Methods We conducted a meta-analysis using data from randomized controlled trials (RCTs) by comparing autologous

BMCs therapy with controls in patients with critical limb ischemia, and the primary endpoint is the incidence of amputation.

Pubmed, EBSCO and the Cochrane Central Register of Controlled Trials (to approximately July 25, 2012) were searched.

Results Seven RCTs with 373 patients were enrolled in the meta-analysis. Because serious disease was the main

reason leading to amputation in one trial, six studies with 333 patients were finally included in the meta-analysis. Pooling

the data of the final six studies, we found that BMCs therapy significantly decreased the incidence of amputation in

patients with CLI (odds ratio (OR), 0.37; 95% confidence interval (CI), 0.22 to 0.62; P=0.0002), and the efficacy had not

significantly declined within 6 months after BMCs were transplanted; OR, 0.33; 95% CI, 0.16 to 0.70; P=0.004 within 6

months and OR, 0.30; 95% CI, 0.11 to 0.79; P=0.01 within 3 months. The rate of AFS after BMCs therapy was

significantly increased in patients with Rutherford class 5 CLI (OR 3.28; 95% CI, 1.12 to 9.65; P=0.03), while there was

no significant improvement in patients with Rutherford class 4 (OR 0.35; 95% CI, 0.05 to 2.33; P=0.28) compared with

controls. The BMCs therapy also improved ulcer healing (OR, 5.83; 95% CI, 2.37 to 14.29; P=0.0001).

Conclusions Our analysis suggests that autologous BMCs therapy has a beneficial effect in decreasing the incidence

of amputation and the efficacy does not decrease significantly within 6 months after BMCs transplantation. Patients with

Rutherford class 5 are suitable for BMCs therapy, while the efficiency in patients with Rutherford 4 needs further

evaluation.

Chin Med J 2012;125(23):4296-4300

ritical limb ischemia (CLI) is the most severe

manifestation of peripheral arterial disease (PAD)

and is associated with death, amputation, and a quality of

life similar to that of patients with terminal cancer.1,2

Despite surgical and endovascular recanalization that can

improve perfusion, pain, quality of life, and limb

preservation in the majority of patients with CLI, there

are still 25% to 40% of CLI patients who have exhausted

their therapeutic options and are not candidates for

revascularization: the no-option CLI (NO-CLI) group.3-5

Many approaches have been employed in these patients.

And a few of clinical trails have suggested benefits of

treating CLI with autologous bone marrow stem cells that

include decreased need for major amputation, reduction

of pain, improvements of ulcer healing, ankle-brachial

index (ABI), pain-free walking distance, and

transcutaneous oxygen tension (TcO2). However, the

therapeutic efficacy remains controversial and whether

BMCs therapy is suitable for all CLI patients is unclear.

Therefore, we analyzed pooled data from published,

randomized, controlled trials to assess the efficacy and

safety of autologous bone marrow stem cell

transplantation in patients with CLI.

METHODS Literature search We searched Pubmed, EBSCO, and the Cochrane Central

Register of Controlled Trials for relevant studies

C

DOI: 10.3760/cma.j.issn.0366-6999.2012.23.024 Division of Endocrinology, Department of Medicine (Liu FP, Gao WY, Zhang ZW, Zhou XJ, Yang L, Zhao JY, Yao JM, Liu M and Liao L), Division of Clinical Pharmacy, Department of Pharmaceutical Sciences (Sun SJ), Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China Division of Endocrinology, Department of Medicine, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China (Dong JJ)Correspondence to: Dr. LIAO Lin, Division of Endocrinology, Department of Medicine, Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China (Email: liaolin@medmail.com.cn) LIU Fu-peng and DONG Jian-jun contributed equally to this work.This study was supported by grants from the Natural Science Foundation of Shandong Province (No. Y2008C73, ZR2010HM044), the National Natural Science Foundation of China (No. 81070637), Science and Technology Development Program of Shandong Province (No. 2010GSF10228), Clinical Medical Scientific Research Foundation of Chinese Medical Association (No. 0910340189).

Chin Med J 2012;125(23):4296-4300

4298

hyperlipidemia, and ischemic heart disease, were

significantly higher in the control group than in the cell

therapy group; P=0.040, P=0.011, P=0.044, respectively.

In the trial by Walter et al,9 the four patients who

underwent amputation were the patients with Rutherford

class 6. For those patients, amputation is almost

inevitable. So we determined the article had a C grade

summary score and eliminated this trial.

Baseline characteristics of RCTs enrolled in the meta-analysis Table 2 describes the baseline characteristics of the six

RCTs included in the meta-analysis. One trial did not

mentioned the baseline characteristics of patients and the

number of cells infused.14

Patients with CLI were treated

with different BMCs, including bone-marrow-derived

mononuclear cells (BMMNCs), bone marrow

mesenchymaal stem cells (BMMSCs), and

G-CSF-mobilized peripheral blood mononuclear cells

(PBMNCs), with the number of cells infused range from

1.36×108 to 3.23×10

9. One trial was a three arm

comparison, comparing the therapeutic effects of

BMMSC, BMMNC, and controls.10

We stratified this trial

into BMMSCs and BMMNCs arms, and the corrections

led to only small changes in the summary measures.15

The control arms of the included trials got conventional

medical therapy and/or sham injections.

Meta-analysis of the efficacy We analyzed the OR in incidence of amputation between

cell therapy and control groups at the end of follow-up.

The incidence of amputation among the three hundred

and thirty three patients from the six RCTs trials was

significantly decrease compared with controls (OR, 0.37;

95% CI, 0.22 to 0.62; P=0.0002, Figure 2A).8,10-14

The

heterogeneity test showed no heterogeneity between the

individual studies (P=0.58; I2=0%).

We assessed the therapeutic efficacy with the incidence of

amputation at the end of three and six months after BMCs

transplantation. It did not significantly decline at the end

of three months (OR, 0.30; 95% CI, 0.11 to 0.79; P=0.01,

Figure 2B,) and six months (OR, 0.33; 95% CI, 0.16 to

0.70; P=0.004, Figure 2C). There was no significant

difference in heterogeneity among the individual studies

(P=0.48, I2=0%; P=0.68, I

2=0).

Two trials reported AFS in cell therapy and control

groups according to the Rutherford classification.8,11

The

rate of AFS in patients with Rutherford class 5 was

significantly increased (OR 3.28; 95% CI, 1.12 to 9.65;

P=0.03, Figure 2D), while there was no obvious

difference in patients in Rutherford class 4 (OR 0.35;

95% CI, 0.05 to 2.33; P=0.28, Figure 2E) compared with

controls.

We also tried to analyze the endpoints of ulcer healing,

ABI, pain-free walking distance, TcO2, and the scale of

resting pain. Except for ulcer healing, few trials9,10,13

provided detailed date of the rest endpoint index. So we

analyzed the efficiency of ulcer healing only. Cell therapy

significantly helped ulcer healing (OR, 5.83; 95% CI, 2.37 to 14.29; P=0.0001, Figure 2F), and there was no

significant difference in heterogeneity among the

individual studies (P=0.55; I2=0%). The data provided by

the three trials also showed that the BMCs therapy had a

beneficial effect on ABI, pain-free walking distance,

TcO2, and scale of resting pain.

Sensitivity and publication bias analysis We further explored the therapeutic effects of amputation

by sensitivity analysis. Before we eliminated the trial by

Walter et al,9 the heterogeneity test (P=0.13; I

2=33%)

indicated that the inclusion of patients with Rutherford

class 6 probably was a source of heterogeneity. The

Procházka et al12

trial had an high weight of 34.8% in our

meta-analysis and the number of patients with diabetes,

hyperlipidemia, and ischemic heart disease, were

significantly higher in the controls and all of them may

influence the analysis result. With removing this trial, the

decrease in the incidence of amputation remained

significant (OR, 0.38; 95% CI, 0.20 to 0.73; P=0.004).

The visually symmetrical funnel plots indicated that there

was no obvious publication bias in the RCTs enrolled in

the meta-analysis (Figure 3).

Safety and side effects Generally, bone marrow cell therapy appeared to be safe

and well tolerated. The proportion of adverse events in

treated and control groups was the same, and most side

effects that occurred in these RCTs were short-term

episodes of slight pain, bleeding or hematoma at the bone

marrow aspiration sites associated with bone marrow cell

isolation.10

Study patients experienced a mean decrease in

hematocrit of 2.6% compared with controls, associated

with no hemodynamic instability, and required no specific

therapy.11

One patient experienced moderate cellulitis in

the treated limb after bone marrow aspiration but prior to

Table 2. Basal characteristics of included RCTs

Author (Ref) Sample

size

Mean age

(years) Therapy

Number of cells

infused Comparator arm

Follow-up

(months)

Powell 2012 48/24 69.2/67.3 BMMNC 1.36×108 Standard care + electrolyte solution 12 months

Lu 2011 21/41 limbs 63 BMMNC 9.3×108 Standard care +NS 6 months

Lu 2011 20/41 limbs 65 BMMSC 9.6×108 Standard care +NS 6 months

Benoit 2011 34/14 72.5/65.7 BMMNC 3.23×109 Standard care + dilute blood 6 months

Procházka 2010 42/54 66.2/64.1 BMMNC 1.96×108 CD4+ Standard care 4 months

Bar 2006 14/15 Unclear BMMNC Unclear Standard care 6 months

Huang 2005 23/24 71.1/70.9 G-CSF mobilized PBMNC 3×109 Standard care + intravenous prostaglandin E1 3 months

Chinese Medical Journal 2012;125(23):4296-4300

4299

Figure 2. Forest plot of OR with 95% CI in amputation (A), amputation within 3 months (B), amputation within 6 months (C), AFS of patients with Rutherford class 5 (D), AFS of patients with Rutherford class 4 (E) and ulcer healed (F).

therapeutic cell injections, and one patient had a severe

localized infection of the first toe of the treated limb

recorded on study day 34 that was resolved by study day

63. Both of the adverse events were “unrelated” or

“unlikely related” to treatment, but were attributed to the

underlying disease.6 No other rejection, allergic reactions,

Figure 3. Publication bias.

inappropriate angiogenesis, or tumorigenesis were

detected due to transplantation of the cell products.

DISCUSSION

The main finding of our study is that BMCs therapy

significantly decreases the incidence of amputation in

patients with CLI and the efficacy is not significantly

decreased at 6 months after BMCs transplanted. The

efficacy of BMCs therapy on AFS is improved in patients

classified as Rutherford 5. For patients with a Rutherford

4 classification, the efficacy needs further confirmation

by more clinical trials. Meanwhile, BMCs therapy has a

beneficial effect on other physiologic and anatomic

parameters, including ulcer healing, ABI, pain-free

walking distance, TcO2, and the scale of resting pain. So,

BMCs therapy might be a good choice for patients with

CLI of Rutherford class 5.

Many factors may influence the efficacy of BMCs

therapy. The influence of cell types, delivery routes, and

methods used for mononuclear cell separation have been

discussed in some studies.10,16-18

And none of these

elements show significant advantages in decreasing the

incidence of amputation and increasing the rate of AFS.

By analyzing the RCTs we find that the condition of the

patient plays an important role in the final result; the cell

therapy group has no advantages for AFS in CLI patients

of Rutherford class 4 compared with controls. Besides the

small sample size, the condition of patients with

Rutherford class 4 is another reason to influence the

efficacy; Rutherford class 4 is not severe enough to

stimulate BMCs to play significant therapeutic action. On

the other hand, if the condition of patients is too serious,

we can not hope that BMCs therapy can change the final

outcome. Under such circumstances, there is also no

obvious improvement between cell therapy groups and

controls. For patients of Rutherford class 6, amputation is

almost inevitable. In the trial by Walter et al, all the

patients with Rutherford class 6 underwent amputation

Figure 2. Forest plot of OR with 95% CI in amputation

Meta-analysis of the efficacy

We analyzed the OR in incidence of amputation between

cell therapy and control groups at the end of follow-up. The

incidence of amputation among the three hundred and thirty

three patients from the six RCTs trials was significantly

decrease compared with controls (OR, 0.37; 95% CI, 0.22

to 0.62; P=0.0002, Figure 2A).8,10-14 The heterogeneity

test showed no heterogeneity between the individual

studies (P=0.58; I2=0%).

SAFETY AND EFFICACY OF ACT IN CLI 5

than half the patients had diabetes (53.5%) and tissue loss

(69.4%). While 13.7% of the overall population required

dialysis, this number is largely influenced by a single trial

by Horie et al., in which two thirds of the patients (108

of 162) were on dialysis (27). Excluding this trial, the

overall dialysis rate was 5.8%.

Etiology

Atherosclerosis was the most common cause of CLI,

and 27 trials presented data on ASO patients. Nine tri-

als presented data on TAO patients and five trials did not

record the specific etiology of limb ischemia. Twelve tri-

als enrolled a mixed population, but four of these pre-

sented their results separately based on etiology and

those are included in the numbers of ASO and TAO trials

above. ASO patients were older, had significantly higher

rates of diabetes and renal failure when compared to TAO

patients, although both groups had similar rates of tissue

loss (Table 3).

Cell Source

The majority of cell therapy trials in the literature used

bone marrow-derived cells. In the BMMNC group, there

were 35 trials (6 RCTs, 3 cohort trials, 26 case series) that

enrolled 1123 patients, 891 who received cell therapy,

and 232 who served as controls. In the PBMNC group,

11 PBMNC trials (one RCT and 10 cases series) enrolled

395 patients with 381 treatment patients and 14 con-

trols. One trial by Huang et al., compared BMMNCs

and PBMNCs in separate arms; therefore, the sum of

BMMNC and PBMNC trials is greater than the total

number of published trials (31).

The mean volume of bone marrow aspirate in the

BMMNC protocols was 386 ml (50–750 ml). One of the

50-ml protocols used culture expansion to increase cell

counts.

Of the 10 PBMNC trials, nine pretreated patients with

G-CSF to promote stem cell mobilization to the periph-

eral circulation prior to apheresis for collection of cells.

Figure 1. Flow chart of systemic review of cell therapy in no option critical limb ischemia (CLI).

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12 BENOIT, O’DONNELL, AND PATEL

12.2%, p < 0.0001). Trials in which greater than 50% of

patients had tissue loss had a significantly higher amputa-

tion rate than those with a lesser proportion of tissue loss

(16.8% vs. 7.7%, p = 0.0096). In patients with atheroscle-

rosis, trials with a mean age of greater than 67 years (the

mean age of all ASO patients) had a significantly higher

amputation rate than trials with a younger proportion of

patients (25.0% vs. 17.3%, p = 0.0074). This influence

of age on amputation rate was not seen in patients with

thromboangiitis obliterans.

To best estimate the efficacy of cell therapy on ampu-

tation rate, we focused our detailed analysis to RCTs. The

duration of follow-up in the RCTs was similar (mean 4.1

months, range 1–6 months), which facilitated comparison

of amputation rates among these trials.

In the seven RCTs, patients receiving cell therapy had

a significantly lower amputation rate than control patients

(14.4% vs. 27.6%, p = 0.0019). Focusing on the five tri-

als using bone marrow protocols alone, the positive

effect of cell therapy persists with an amputation rate of

14.8% in BMMNC-treated patients and 25.4% in controls

(p = 0.0278) (Table 8).

To further estimate the impact of cell therapy on ampu-

tation, we performed a meta-analysis on the seven RCTs.

The odds ratio was 0.36, indicating that patients treated

with cell therapy had a 36% chance of amputation when

compared with control patients (p = 0.0004) (Fig. 2).

Time to Amputation

Although published trials do not present individual

patient data on time to amputation, evaluation of ampu-

tation rates based on trial follow-up offers some insight

into the timing of amputation. As trial duration increases

from 3 to 6 to greater than 12 months, the amputation rate

increases from 8.0% to 24.5% (Table 9). Longer trials pro-

vide more time in which amputations may occur. Looking

at the percentage of total amputations based on trial dura-

tion suggests that amputations do not occur at a steady

rate but are grouped largely in the first 6 months. While

12.3% of amputations occur in trials under 3 months and

41.9% occur in trials under 6 months, 49.8% of ampu-

tations occur in trials under 12 months. From this, we

can infer that most amputations may take place within 6

months of enrollment with a prolonged “tail” of ampu-

tations occurring as follow-up progresses. This suggests

that cell therapy trials with duration of 6 months may cap-

ture sufficient data with regard to amputation.

Death

There were 119 deaths in the group of 1,272 patients

who received cell therapy, resulting in an overall mortal-

ity rate of 9.4%.

Initial comparison of mortality rates between trials

with different cell sources suggests that BMMNC-treated

patients had a lower mortality than those receiving

PBMNCs (5.5% vs. 18.4%, p < 0.0001). However, these

results are heavily influenced by the trial by Horie et al.,

which had a long follow-up (median 26.4 months) and

a 66.7% dialysis rate, both of which increase the mor-

tality rate (27). Excluding this trial, the mortality rate in

PBMNC trials was 9.1%, which, although higher than the

rate in bone marrow trials, is not significantly different

(p = 0.059).

Mortality rates differed by etiology. Patients with

atherosclerosis had a 12.7% mortality rate while only

0.5% of patients with thromboangiitis obliterans died

(p < 0.0001).

As with amputation, evaluating the effect of risk fac-

tors on mortality is limited to analyzing outcomes in tri-

als with different proportions of a given risk factor. This

analysis suggests that diabetes, dialysis, tissue loss, and

age contribute to higher mortality rates. Trials in which

greater than 50% of patients had diabetes had a signifi-

cantly higher mortality rate than those with a lesser propor-

tion of diabetics (12.5% vs. 3.4%, p < 0.0001). Trials that

enrolled patients with dialysis had a significantly higher

mortality rate than those that had no dialysis patients

(24.0% vs. 4.0%, p < 0.0001). Trials in which greater than

50% of patients had tissue loss had a significantly higher

mortality rate than those with a lesser proportion of tis-

sue loss (10.1% vs. 4.0%, p = 0.050). In patients with ath-

erosclerosis, trials with a mean age greater than 67 years

(the mean age of all ASO patients) had a significantly

higher mortality rate than trials with a younger propor-

tion of patients (18.8% vs. 8.4%, p < 0.0001). This influ-

ence of age on mortality rate was not seen in patients with

thrombo angiitis obliterans.

Again, as with amputation, to estimate the effect of cell

therapy on mortality, we limited our analysis to RCTs. In

the seven RCTs, there was no significant difference in mor-

tality rates between patients who received cell therapy and

controls (4.1% vs. 5.9%, p = 0.475). This lack of difference

in mortality rates was also true of the BMMNC trials alone

(Table 10). While this does not demonstrate efficacy of cell

therapy with regard to improving patient survival, it sup-

ports the fact that cell therapy is a safe procedure.

Table 8. Amputation Rates From RCTs: All Trials Versus

BMMNC Trials Alone

n Pts n Amp % Amp p*

All RCTs 365 75 20.5

Tx 195 28 14.4 0.0019

Control 170 47 27.6

BMMNC 295 58 19.7

Tx 149 22 14.8 0.0278

Control 142 36 25.4

*Value of p is calculated using Fischer ’s exact test.

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A: Major amputationB: Amputation-free survival

B

A

Ann Surg. 2013 Dec;258(6):922-9.

Výsledky 5 meta analýz pro amputace a hojení ran

[1] Wang, Zheng-Xu, et al. "Efficacy of Autologous Bone Marrow Mononuclear Cell Therapy in Patients

with Peripheral Arterial Disease." Journal of atherosclerosis and thrombosis (2014).

[2] Fadini, Gian Paolo, Carlo Agostini, and Angelo Avogaro. "Autologous stem cell therapy for

peripheral arterial disease: Meta-analysis and systematic review of the literature." Atherosclerosis 209.1

(2010): 10-17.

[3] Liu, F. P., et al. "Autologous bone marrow stem cell transplantation in critical limb ischemia: a meta-

analysis of randomized controlled trials." Chinese medical journal 125.23 (2012): 4296-4300.

[4] Teraa, Martin, et al. "Autologous Bone Marrow–Derived Cell Therapy in Patients With Critical Limb

Ischemia: A Meta-Analysis of Randomized Controlled Clinical Trials." Annals of surgery 258.6 (2013): 922-

929.

[5] Benoit, Eric, Thomas F. O'Donnell, and Amit N. Patel. "Safety and efficacy of autologous cell therapy

in critical limb ischemia: a systematic review." Cell transplantation 22.3 (2013): 545-562.

Meta studie pokrývají klinická hodnocení (KH) mezi roky 2002-2013 a zahrnují cca 1500 jedinečných pacientů. Zahrnutéstudie jsou převážně randomizované studie z nichž velká část jsou kontrolované studie (versus placebo nebo běžná péče).

Výsledky meta analýz pro amputace a hojení ran

A) Hard endpoints

[1] Amputace rok 1 OR=8.05 CI95% (3.58 - 18.08) P < 0.00001

Amputace rok 3 OR=22.33 CI95% (4.14 - 120.5) P = 0.0003

[2] Amputace OR=11.11 CI95% (2.27 - 50.00) P = 0.0005

Hojení ran OR=3.54 CI95% (1.09 - 11.51) P = 0.032

[3] Amputace OR=2.70 CI95% (1.61 - 4.45) P = 0.0002

Hojení ran OR=5.83 CI95% (2.37 - 14.29) P = 0.0001

[4] Amputace RR=0.45 CI95% (0.27 - 0.75) P = 0.002

Hojení ran RR=1.87 CI95% (1.49 - 2.36) P = 0.00001

[5] Amputace OR=2.77 P = 0.0004

Hodnoty hard endpointů (amputace a hojení) jsou ve studiích umocněny

konzistentními hodnotami, indikujicími zlepšení, ve vedlejších endpointech

jako ABI, bolest, tcpO2. Dále homogenita výsledků přesahuje jednotlivé

studie a je patrna i v podobnosti hodnot OR a RR pro amputace a hojení

mezi studiemi.

Výsledky meta analýz pro amputace a hojení ranB) Surrogate Endpoints

[1] ABI 12 týdnů MD 0.12 CI95% (0.07 - 0.16) P<0.00001

ABI 24 týdnů MD 0.14 CI95%(0.10 - 0.17) P<0.00001

ABI 48 týdnů MD 0.12 CI95%(0.02 - 0.23) P=0.02

TcpO 12 týdnů MD 1.95 mmHg CI95%(−7.41-11.3) P=0.68

TcpO2 24 týdnů MD 6.89mmHg CI95%(6.17 -7.62) P＜0.00001

TcpO2 48 týdnů MD 20.35mmHg CI95%(12.51-28.19) P＜0.00001

Bolest MD −1.37 CI95%(−1.69-−1.04) P < 0.00001

[2] ABI 0.46 ± 0.04 0.63 ± 0.04 P = 0.011

TcpO2 22.8 ± 2.8 35.8 ± 2.9 P = 0.0002

Bolest 6.35 ± 0.43 2.11 ± 0.37 p < 0.0001

Klaudik. interval 75.7 ± 19.4 402.3 ± 70.9 p < 0.0001

[4] ABI 0.12 CI95%(.09,.15) ~+30% P < 0.00001

TcpO2 14.26mmHg CI95%(8.54,20.02) ~+30% P < 0.00001

Bolest -1.1 CI95%(-1.37,-.83) ~+25% P < 0.00001

Klaudik. interval 178.73m CI95%(127.68,229.78) P < 0.00001

[5] ABI zlepšení u 24 (studií) z 38 +63.2%

TcO2 zlepšení u 20 (studií) z 26 +76.9%

Bolest zlepšení u 33 (studií) z 37 +89.2%

Klaudik. interval Zlepšení u 17 (studií) z 19 +89.5%

Výsledky meta analýz pro amputace a hojení ran

C) Vyjádření autorů k bezpečnosti aplikace buněčné terapie

[1]”The majority of adverse events were associated with hospitalization for disease process-related

complications, not complications related to cell therapy, including pain in the extremities and

gastrointestinal disorders that were unrelated to the cell therapy.”

[2]”The procedures were well tolerated and generally safe”

[3]”Generally, bone marrow cell therapy appeared to be safe and well tolerated. The proportion of

adverse events in treated and control groups was the same”

[4]”In the considered RCTs, BM-derived cell therapies appeared relatively safe and side effects were

generally mild and transient.”

[5]” Cell therapy presents a favorable safety profile with a low adverse event rate and no increase in

severe events such as mortality and cancer and treatment with cell therapy decreases the risk of

amputation”

Development of Stem Cell PreparationsRisk Based Approach

Stem Cell-Type, Degree and Type of ManipulationAutologous vs. Allogenic concept and intended use determine risk

assessment.

SOURCE: EU ATMP POSITION REFLECTION PAPER

Primary SC (HSC, MSC, MNC)

Expanded(Cell Lines, SC’s (MSC)

Manipulated / PreconditionedSC’s (HSC, MSC)

GeneticallyManipulatedSC’s (HSC, MSC)

inVitroReprogammedSC’s

inVitroEstablishedCell Lines

Adult SC’s (intrinsic SC Pool): Multipotent

iPSC(Pluripotent)

ESC(Pluripotent)

Low

High

BMAC

Regulatory StatusUSA: FDA 510K Cleared, EU: CE Mark with Expansion Claim

Souhrnvykázané/uznanépéčezapacienty,kteříprodělaliamputacikvůliporušeoběhovéhosystému,

kroměhorníchkončetinaprstůunohy,vizDRGbáze0515-dataza01/2011-10/2014(hosp.datadleDRG;preskripceapoukazynazdrav.prostředky;amb.produkce)

-zdrojdat:Archívvykázané/uznanépéčeFNO(datovýskladOSVZPaOFA)

ROK

počet RČ dle

DRG báze

0515 body LP Zum, Zulp

HOSP.-

výkonověsHB

0,90Kč CM

ÚhradaHOSP.-vše

přesPřípadový

paušálDRG(předi

poamputaci)

počet RČ

dle DRG

báze 0515

(před i po

amputaci) HVLP IVLP ZP

PreskripceLékůaZP

pac.(předipo

amputaci)

počet RČ dle

DRG báze 0515

(před i po

amputaci) body Zum,Zulp

ÚhradaAMB.(před i po

amputaci)

2011 67 6 694 648 173 570 Kč 1 291 037 Kč 7 489 790 Kč 247,4431 7988940Kč 76 708 940 Kč 0 Kč 446 666 Kč 1155606Kč 97 2 550 391 481 640 Kč 2536251Kč

2012 61 6 277 889 165 970 Kč 1 543 014 Kč 7 359 084 Kč 228,9441 7727830Kč 76 833 484 Kč 0 Kč 507 724 Kč 1341208Kč 88 2 791 178 420 305 Kč 2648800Kč

2013 70 7 075 759 198 465 Kč 1 870 630 Kč 8 437 278 Kč 273,6646 8706160Kč 68 526 295 Kč 0 Kč 337 734 Kč 864029Kč 94 2 400 561 685 029 Kč 2571565Kč

01-10/2014 52 5 443 352 129 240 Kč 1 351 064 Kč 6 379 320 Kč 185,3878 6106743Kč 55 445 878 Kč 0 Kč 267 377 Kč 713254Kč 73 694 910 118 054 Kč 686750Kč

Celkem 25 491 648 667 245 Kč 6 055 744 Kč 29 665 472 Kč 935,4396 30529673Kč 2 514 597 Kč 0 Kč 1 559 501 Kč 4074097Kč 8 437 040 1 705 028 Kč 8443366Kč

*r.2011-2013-výpočetdlevyúčtovánízdrav.služebodjednotlivýchZP-všePřípadovýmpaušálem(jakoAlfaDRG); **bodypřepočtenék1.1.2014;úhradazabodydleHBdleúhradovévyhlášky(HBnesnižována)

r.2014-dleÚhradovévyhlášky-všePřípadovýmpaušálem(jakoAlfaDRG) včetněvýkonů:klinickéstomatologie;CyberKnife;SDH;lůžeksociálnípéče;foniatrickýchpomůcek

ROK prům. HOSP.

prům.

PRESKR. prům. AMB.

Váženáprům.

úhradanaRČ

(Hosp,Preskr.,

Amb.)

2011 119238Kč 15205Kč 26147Kč 160590Kč

2012 126686Kč 17647Kč 30100Kč 174433Kč

2013 124374Kč 12706Kč 27357Kč 164437Kč

01-10/2014 117437Kč 12968Kč 9408Kč 139813Kč

Cenaprotézy: 85tisKčCenavozíku: 40tisKč

PRESKRIPCEHVLP,IVLPaZPnapoukaz AMBULANCE**HOSPITALIZACEdleDRG

Průměr = 166 500 kč

Protéza= 85 000 kč

Vozík = 40 000 kč

Celkem= 291 500 Kč

Náklady na rehabilitaci

Socio-ekonomické náklady

EURODIALE – 500 600 kč

Tabulka 1 Počty pacientů s diabetem a výskyt vybraných komplikací v letech 2000-2013

Pacienti s DM v daných letech1 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Počet léčených pacientů celkem

k 31.12. daného roku 654 164 653 418 667 135 686 865 712 079 739 305 748 528 754 961 773 561 783 321 806 230 825 382 841 227 861 647

Počet léčených pacientů na

100 000 obyv. 6 368 6 391 6 540 6 733 6 976 7 224 7 291 7 314 7 417 7 466 7 666 7 863 8 005 8201

Počet nově zjištěných

onemocnění 52 649 52 375 51 644 56 683 54 303 56 545 56 311 56 398 55 975 61 357 64 997 68 494 72 063 72 600

Počet nově zjištěných

onemocnění na 100 000 obyv. 513 512 506 556 532 553 548 546 537 585 618 653 686 691

Počet úmrtí - celkem2 22 852 23 460 23 421 24 603 23 725 23 326 23 521 22 869 22 259 21 747 22 286 23 290 23 886 25 508

Počet úmrtí – ve vztahu k DM3 13 037 11 983 11 470 11 436 11 269 11 154 10 759 10 990 11 061 10 821 11 502 12 369 11 915 -

Diabetická noha - celkem 37 764 36 725 38 166 37 971 39 753 38 090 41 328 42 337 42 992 43 990 45 118 44 011 43 248 44 657

s amputací 5 865 6 118 6 743 7 029 7 444 7 303 7 834 7 853 8 169 8 439 8 501 10 408 10 425 11 168

nad kotníkem - - - - - -

- - - - 6 469 6 390 6 899

pod kotníkem - - - - - -

- - - - 3 939 4 035 4 269

Náklady na pacienty s DM

s amputací I 4 (mil. Kč) 976 1 019 1 123 1 170 1 239 1 216 1 304 1 307 1 360 1 405 1 415 1 733 1 736 1 859

Náklady na pacienty s DM s amputací I I 5 (mil. Kč)

1 475 1 539 1 696 1 768 1 872 1 837 1 970 1 975 2 054 2 122 2 138 2 617 2 622 2 809

1 zdrojem dat je „Výkaz o činnosti zdravotnických zařízení pro obor diabetologie (A04)“, diabetes je definován jako E10, E11, E13, R73.0

2 Úmrtí z jakékoliv příčiny u pacientů s DM (dle A04)

3 DM uveden mezi příčinami úmrtí pacientů (dle Listu o prohlídce zemřelého); rok 2013 nezobrazen z důvodu nekonzistence sběru dat (v období 2000-2012 může být v

datech LPZ uvedeno celkem 6 dg. (3 hlavní, 3 vedlejší), v datech za rok 2013 může být uvedeno až 40 diagnóz). 4 Na základě průměrných nákladů z let 2011-2013 za pacienty s DM s amputací (bez protézy) a počtu pacientů s amputací v daném roce

4 Na základě průměrných nákladů z let 2011-2013 za pacienty s DM s amputací (včetně protézy) a počtu pacientů s amputací v daném roce

Závěr (1)

Pojem “Lege artis” je chápán jako označení postupu, který je

v souladu s obvyklými, obecně uznávanými metodami určitého

vědního oboru, případně umění.

Pojem “LEGE ARTIS” není v platných právních předpisech

definován. Jakýkoliv zákrok v oblasti péče o zdraví, včetně

vědeckého výzkumu, je nutno provádět v souladu s příslušnými

profesními povinnostmi a standardy.

Na základě doporučení České angiologické společnosti a České

diabetologické společnosti ČLS J. E. Purkyně, je léčba kritické

končetinové ischemie autologním koncentrátem kostní dřeně při

intramuskulárním podání bez podstatné manipulace metodou lege artis.

Závěr (2)

Pro realizaci výkonu je použit zdravotnický prostředek Harvest

Technologies Corp (SmartPreP2) certifikační list CE 61857, certifikát

BSI k výkonu NO-CLI. Zdravotnický prostředek použitý k výkonu má

certifikát v souladu s platnými předpisy ČR i EU.

Výkon může být prováděn pouze na specializovaném pracovišti při

hospitalizaci, kde existuje tkáňové zařízení určené k odběru,

zpracování, propouštění a kontrole kvality koncentrátu kostní

dřeně.

Na základě předmětného povolení jsou FN Ostrava, tak IKEM-Praha,

oprávněny za podmínek zákonem stanovených takto připravovat kostní

dřeň pro léčbu NO-CLI.

Závěr (3)

Léčivé přípravky pro buněčnou terapii se řídí zákony zák.č. 296/2008Sb. (Zákon o lidských tkáních a buňkách, “ZoLTB”) a zák.č.378/2007 Sb (Zákon o léčivech, “ZoL”).

V rámci výkonu nedochází k žádným manipulacím, jako napříkladkultivace buněk nebo enzymatické rozvolnění, která by byla nařízenímoznačena za manipulaci zásadní. Je zachována stejná funkce, neboťdochází k revaskularizaci ischemické tkáně.

Ke stejnému závěru dospěl i SÚKL ve svém stanovisku ze dne31.12. 2008 pro FN Ostrava a zároveň v obecné rovině ze stanoviskaÚstavu ze dne 14. 6. 2012 dostupného na:

http://www.sukl.cz/zdravotnicka-zarizeni/stanovisko-sukl-k-pouziti-autolognich-kmenovych-bunek

Závěr (4)

Metaanalýzy klinických hodnocení (KH) publikovaných mezi roky 2002-

2014 zahrnující cca 1500 jedinečných jedinců, představují analýzu

publikací druhé nejčastější indikace transplantací kmenových buněk

po nehematoonkologických onemocněních.

Zahrnuté studie jsou převážně randomizované, kontrolované studie

(kde komparátorem je placebo nebo standardní léčba).

Sledované “Hard endpoints” tak i “Surrogate endpoints” zcela

přesvědčivě dokumentují bezpečnost a účinnost léčby transplantací

autologní kostní dřeně pro léčbu kritické končetinové ischemie bez

možnosti revaskularizace.

Závěr (5)

Léčba tak jak je navrhována registračním listem je “Cenově přijatelná”

ve srovnání s náklady na amputaci pacienta v bérci či ve stehni a z

hlediska etického představuje poslední možnost před hrozící amputací

končetiny.

Léčba je určena pro přísně vybranou skupinu pacientů s NO-CLI na

specializovaných pracovištích, (Efektivita pro “Limb salvage and wound

healing” - 60-70%).