No Clinical Benefit of Intramuscular Delivery of Bone Marrow-derived Mononuclear Cells in Nonreconstructable Peripheral Arterial Disease: Results of a Phase-III Randomized-controlled Trial.

BACKGROUND AND AIMS: Prospects for no-option, end-stage peripheral artery disease (PAD) patients remain poor. Although results from open and semiblinded studies fuel hope for cell-based strategies in no-option patients, so far conclusions from the available placebo-controlled studies are not supportive. With the intention to end the remaining controversy with regard to cell therapy for PAD we conducted a confirmatory, double-blinded randomized placebo-controlled phase 3 trial. STUDY DESIGN: This randomized controlled trial was registered (NCT00539266). Inclusion criteria included stable or progressive disabling PAD, no imminent need for amputation, absent accepted options for revascularization. Diabetic disease was an exclusion criterion. Bone marrow (500-700 mL) was harvested and bone marrow-derived mononuclear cells were concentrated to 40 mL. Concentrated cells or placebo (diluted blood) were intramuscularly injected at 40 locations of the calf muscle. RESULTS: Fifty-four patients (mean (sd) age 58.2 (14.2) yrs, 58% males) were randomized. Twenty-eight patients received BM-MNCs, 26 placebo. Baseline criteria were similar in the 2 groups. No significant differences were observed for the primary (number of amputations, (pain free) walking distance) and secondary outcome parameters (ankle brachial index, pain scores, quality of life (SF-36)). DISCUSSION: This fully blinded replication trial of autologous BM-MNC fails to confirm a benefit for cell therapy in no-option PAD patients, consequently BM-MNC therapy should not be offered as a clinical treatment. Apparent contrasting conclusions from open and controlled studies underscore the importance of a controlled trial design in evaluating cell-based interventions in PAD.

Aneurysm sac pressure monitoring: does the direction of pressure measurement matter in fibrinous thrombus?

PURPOSE: This study was conducted to clarify the effect of the direction of pressure measurement on the pressure readout in fibrinous thrombus of the abdominal aortic aneurysm. METHODS: Three weights of 468 g (weight 1), 578 g (weight 2), and 675 g (weight 3) were molded. A specimen of human fibrinous thrombus was positioned under the weights. Because the surface area of the weights and the thrombus was 400 mm(2), weights 1, 2, and 3 caused pressures of 88, 108, and 127 mm Hg, respectively. Pressure measurements were performed at different angles between the sensor and the applied force (0 degrees , 22.5 degrees , 30 degrees , 45 degrees , 60 degrees , 67.5 degrees , 90 degrees ) Thrombi of 10 different patients were analyzed. Pressure measurements in the thrombi at different angles were statistically compared by a linear mixed model analysis. RESULTS: The measurements at 90 degrees differed statistically from the measurements at 0 degrees , 22.5 degrees , 30 degrees , 45 degrees , 60 degrees , and 67.5 degrees (P < .001). The pressure readout was only similar to the applied pressure when the pressure sensor was positioned at 90 degrees to the applied force. Pressure measurements in other sensor positions resulted in lower pressure measurements. Pressure changes were detected in all sensor positions. There appeared to be no significant difference between the pressure measurements taken at same angles in the 10 thrombi (P > .05). CONCLUSION: In fibrinous thrombus of abdominal aortic aneurysm, the direction of pressure measurement influenced the pressure readout.

Effect of intraluminal thrombus on pressure transmission in the abdominal aortic aneurysm.

OBJECTIVE: To clarify the effect of intraluminal thrombus on pressure transmission. METHODS: A saccular aneurysm was inserted into an artificial circulation system. Subsequently, the saccular aneurysm was filled with eight different human aortic aneurysm thrombus samples. Starch solution in an empty aneurysm was used as a control. A pressure sensor measured the pressure in the circulation, and a second piezoelectric sensor measured the pressure in the saccular aneurysm at 3, 2, and 1 cm from the endoluminal surface (23 locations). The influence of the elastic characteristics of the aneurysm wall on the extent of pressure reduction was evaluated by experiments performed with aneurysms made of rubber and paraffin. RESULTS: The pressures measured in the empty aneurysm were identical to those measured in circulation (P > .05). The pressure measured in the thrombus was significantly lower than the pressure measured in the circulation (P < .05). The mean pressure ratio between the systolic thrombus pressure and systolic circulation pressure at 1, 2, and 3 cm was 0.90 +/- 0.09, 0.86 +/- 0.10, and 0.81 +/- 0.09, respectively. However, there was a clear correlation between the pressure in the circulation and in the thrombus (Pearson correlation coefficient: mean, r = 0.997; range, 0.975-0.999; P < .01). The change in circulatory pressure was followed by an almost identical change in thrombus pressure (regression coefficient: mean, beta = .997; range, .983-1.000; P < .01). In stiff aneurysms, the pressure reduction is less than in more compliant ones (P < .05). CONCLUSIONS: In an in vitro model, pressure in the aneurysmal sac is reduced by fibrinous thrombus. CLINICAL RELEVANCE: Endovascular aneurysm repair (EVAR) aims at reducing the pressure in the aneurysmal sac. Therefore, it seems attractive to use pressure monitoring in the aneurysmal sac as a follow-up after EVAR. This study contributes to the development of the rationale of pressure monitoring in the aneurysmal sac as a follow-up method after EVAR. The aneurysmal sac is filled with thrombus. To interpret pressure measurements in the thrombus, we have to learn about the effect of the thrombus on pressure transmission and on the pressure measurements themselves. Our study demonstrates that reduction of pressure occurs as it is transmitted through a human aortic thrombus.