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Intra-arterial administration of Bone- marrow mononuclear cells in patients with critical limb ischemia – a randomized placebo-controlled trial PROVASA.

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Presentation on theme: "Intra-arterial administration of Bone- marrow mononuclear cells in patients with critical limb ischemia – a randomized placebo-controlled trial PROVASA."— Presentation transcript:

1 Intra-arterial administration of Bone- marrow mononuclear cells in patients with critical limb ischemia – a randomized placebo-controlled trial PROVASA Intra-arterial administration of Bone- marrow mononuclear cells in patients with critical limb ischemia – a randomized placebo-controlled trial PROVASA D.H.Walter, H. Krankenberg, J. Balzer, C. Kalka, I. Baumgartner, M. Schlüter, T.Tonn, F.Seeger S.Dimmeler, E.Lindhoff-Last, A.M.Zeiher MVZ Prof. Mathey, Prof. Schofer, Hamburg, Cardiology - Angiology and Radiology, Frankfurt Inselspital Bern Blutspendedienst Hessen ClinicalTrials.gov number : NCT D.H.Walter, H. Krankenberg, J. Balzer, C. Kalka, I. Baumgartner, M. Schlüter, T.Tonn, F.Seeger S.Dimmeler, E.Lindhoff-Last, A.M.Zeiher MVZ Prof. Mathey, Prof. Schofer, Hamburg, Cardiology - Angiology and Radiology, Frankfurt Inselspital Bern Blutspendedienst Hessen ClinicalTrials.gov number : NCT

2 I do not have any potential conflict of interest

3 Intra-arterial Application of Bone-Marrow Mononuclear Cells Isolation of mononuclear cells (Ficoll) BSD Hessen GMP Facility Bone-marrow (50 ml, Local anesthesia) * Intracoronary In PAOD: no randomized placebo controlled trials available PROVASA Background * REPAIR AMI Schächinger V et al. NEJM 2006 Critical limb ischemia Rutherford 4-6 *

4 PROVASA Study Flow Chart 40 Patients R  BMC  Placebo  BMC (Optional  BMC) Extended Protocol Baseline 3 Months ( open-label ) 6 Months 1:1 Long-term F/U Mean 30.2 months (6-57 months ) Randomized-start, placebo controlled, multicenter trial with a cross-over phase

5 PROVASA Endpoints Primary Endpoint Change in ankle-brachial index (ABI) at 3 and 6 months Secondary Endpoint Wound healing Pain reduction Amputation-free survival

6 PROVASA Inclusion/Exclusion Criteria Patients with Fontaine III or IV who were not candidates for interventional or surgical revascularization or who failed to respond to interventional or surgical procedures. PAOD or thrombangitis obliterans (TAO) Exclusion: prior PTA or Bypass < 3 months Creatinine > 2.0 mg/dl at time ot treatment

7 PROVASA Patient Characteristics BMC N=19 Placebo N=21 P Age, years64.4 ± ±16 NS Men16 (84%)13 (62%) NS Hx of smoking10 (53%)10 (48%) NS Current smoker4 (21%)1 (5%) NS Diabetes10 (53%)10 (48%) NS IDDM9 (47%)6 (29%) NS Hypertension14 (74%)14 (67%) NS Hyperlipidemia15 (79%)16 (76%) NS Kidney dysfunction7 (37%)6 (29%) NS Hx of CAD10 (53%)10 (48%) NS Prior MI6 (32%)4 (21%) NS Heart failure (LVEF ≤ 35%)3 (16%)1 (5%) NS

8 PROVASA PAD/Procedural Characteristics BMC N=19 Placebo N=21 P Femoropopliteal occlusion6 (32%)7 (33%) NS Infrapopliteal disease13 (68%)14 (67%) Buerger’s disease (TAO)3 (16%)5 (24%) NS Mediasclerosis5 (26%)3 (14%) NS Rutherford category NS 4 (rest pain)4 (21%)6 (29%) 5 (minor tissue loss)12 (63%)14 (67%) 6 (gangrene)3 (16%)1 (5%) Prior PTA > 3 months prior3 (16%)10 (48%) 0.04 Prior peripheral surgery3 (16%)9 (43%) NS Prior minor amputation3 (16%)2 (10%) NS BMC 3 months14 (74%)19 (90%) NS BMC therapy > 6 months 5 (26%)6 (29%) NS

9 PROVASA Results Ankle-brachial index (1 ry EP) in 26 patients with complete serial measurements BLM3M6 Median ABI IQR P*=0.040 *Repeated measures ANOVA All pts  BMC P**=0.014 **Holm test (post hoc) Pooled data

10 PROVASA Results Ankle-brachial index (1 ry EP) in 26 patients with complete serial measurements BLM3M6 Median ABI IQR BMC (n=11) Placebo (n=15) All pts  BMC P † =0.836 Randomized-Start

11 PROVASA The Primary Endpoint Dilemma ABI values were not useful as primary endpoint Changes in ABI do not correlate well with ulcer healing and limb salvage In patients with thrombangiitis obliterans (TAO) as well as in patients with extensive mediasclerosis, ABI values do not reflect the degree of distal ischemia and tissue necrosis.

12 PROVASA Ulcer Healing- quantitative Analysis Figure 3A BM-MNC (n=10) Placebo (n=12) P=0.014 All BM-MNC Randomized-Start Mean Ulcer Area (cm²) P=0.009 P=0.5 SE P=0.2 P=0.059 P=0.09

13 Mean Reduction of Ulcer Area (cm²) 1x BM-MNC (n=10 ) + (n = 11) Placebo (n=12) 2x BM-MNC (n=19) P=0.16 vs Placebo P=0.018 vs Placebo PROVASA Ulcer Area- Absolute Reduction

14 PROVASA Patients with Complete Ulcer Healing NS P=0.037 All BMC vs. Placebo Mean time to ulcer healing 10.9 months All pts  BMC

15 No difference in complete ulcer healing within 3 months between BMC vs Placebo Complete healing of ulcers 20/30 patients (66.6%) 20/21 (95%) complete healing in patients with stable ulcers, 17/21 (81%) after repeated BMC ! PROVASA Ulcer healing

16 PROVASA Pain Analysis-Serial Values BM-MNC (n=10) Placebo (n=15) P=0.02 All BM-MNC Randomized-Start Pain scale P=0.13 M6M3BL SE P=0.004 P=0.3 P=0.002 P=0.009 P=0.343 P=0.014

17 PROVASA Pain Analysis-Absolute Reduction 1x BM-MNC (n=15 ) + (n = 10) Placebo (n=15) 2x BM-MNC (n=10) Pain scale P=0.002 vs Placebo P=0.1 vs Placebo

18 PROVASA Amputation-free survival Pts at risk All pts  BMC No difference within 3 months (BMC vs Placebo) Maj. amputations in patients with advanced lesions/gangrene Event-free survival 6 M : 76%

19 Cell Number and Functional Capacity (Migration) Cell number Functional capacity Migration Number of Cells x10 6 p =0.016 p =0.003

20 FactorP Exp (B) Hazard 95% CI Age Ulcer size EF Pain at baseline Creatinine < 1.4 mg/dl Buerger’s disease (TAO) Cell number Repeated BM-MNC (≥ 2 applications) Cell function – 1.00 Multivariate Analysis Clinical Improvement (Healing or Pain Reduction)   Repeated BM-MNC administration as well as the number and functionality of administered BM-MNC were significant independent predictors for clinical improvement

21 PROVASA Conclusions (1) Intraarterial administration of BM-MNC significantly promotes ulcer healing and reduces rest pain until 3 months versus Placebo Successful ulcer healing associated with improved limb salvage requires repeated administration of functionally competent BM-MNC Patients with thrombangiitis obliterans generally responded well, critically ill patients with extensive gangrene and impending amputation did not derive any benefit.

22 PROVASA Conclusions (2) Thus, large scale randomized trials are warranted to assess the clinical effect of repeated BM-MNC administration in patients with critical limb ischemia with stable ulcers and/or rest pain. Complete ulcer healing occurred at a mean of 10.9 months after BM-MNC administration To assess potential clinical benefits of cell therapy in patients with critical limb ischemia, a follow-up period of at least 18 months will be required.

23 Frankfurt Kardiologie: D. Walter (Coordinator) A. Zeiher (PI) S. Dimmeler Angiologie: A. Kopalla E. Lindhoff-Last Radiologie: J. Balzer, Institut für Transfusionsmedizin BSD Hessen: T. Tonn Hamburg H. Krankenberg M. Schlüter D. Walter (Coordinator) Bern C. Kalka I.Baumgartner

24 PROVASA Back-up slides

25 Responders Younger age Better ejection fraction Smaller ulcer size (< 2.3 cm², p =0.038) Less rest pain at baseline Better renal function (creatinine < 1.4 mg/dl) TAO (all 8 TAO) responders versus 18 of 32 (56%) atherosclerotic PAOD improved clinically by BM- MNC treatments (P=0.02 TAO vs. PAOD). Patients with gangrene (Rutherford 6) did not respond at all.

26 All BM-MNC Randomized-Start BM-MNC (n=6) Placebo (n=10) TCO 2 (mmHg) P=0.52 P=0.17 P=0.14 P=0.032 P=0.018 P=0.058

27 PROVASA Ulcer Healing- quantitative Analysis Mean Ulcer Area (cm²) All BM-MNC Randomized-Start


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