www.cookmedical.com
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:[email protected]
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: [email protected]) 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%).