The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design

<p>Abstract</p> <p>Background</p> <p>Autologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI). One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP), which is usually combined with mortality for AMP-free survival (AFS). Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control) of 48 patients treated with site of service obtained bone marrow cells (BMAC) as well as a systematic review of the literature.</p> <p>Methods</p> <p>Cells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood). Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss.</p> <p>Results</p> <p>Fifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6%) and those with tissue loss (46.7%), irrespective of treatment group, was significant (p = 0.0029). In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337). The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067). Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain.</p> <p>Conclusions</p> <p>BMAC shows promise in improving AMP-free survival if the trends in this pilot study are validated in a larger pivotal trial. The difference in amp rate between Rutherford 4 & 5 patients suggests that these patients should be stratified in future RCTs.</p

Spinal magnetic resonance imaging with reduced specific absorption rate in patients harbouring a spinal cord stimulation device - A single-centre prospective study analysing safety, tolerability and image quality

BACKGROUND:Spinal cord stimulation (SCS) is an accepted treatment in patients with failed back surgery (FBS), complex regional pain syndrome (CRPS) and persistent radicular pain following surgery. In order to avoid patient hazards or device malfunction manufacturers advise to abstain from magnetic resonance imaging (MRI) in patients with implanted electrodes or pulse generators. METHODS:In a prospective study, 13 patients harbouring an implanted Medtronic Spinal Cord Stimulation (SCS) device underwent MRI (1.5 T) of the lumbar (n = 13), the cervical (n = 2) or the thoracic spine (n = 1) following the development of new spinal symptoms. An adapted MRI protocol was used limiting the transmitted energy and specific absorption rate. Tolerability and safety were assessed by means of a standardized patient evaluation form documenting pain on a visual analogue scale (0-10), neurologic deficit, and discomfort during the scan. In addition, overall satisfaction with the examination procedure was rated on a Likert scale (1-5). Image quality was rated independently and blinded to the presence of a SCS device by the radiologist and the surgeon as equivalent, superior or inferior compared to the standard spine MRI examination. RESULTS:None of the 13 patients investigated by the modified spinal MRI protocol experienced new neurological deficits, worsening of symptoms or a defect/malfunction of the implant device. Three patients (23.1 %) reported transient warm sensation in the location of the electrode and in one case intermittent slight tingling in the lower extremities. Overall satisfaction with the examination was 1.13 ± 0.34 according to Likert scale (1-5). The image quality was rated - not statistically significant - slightly inferior to standard lumbar spine imaging (0.82 ± 0.54) with a kappa value of 0.68 between the two investigators. MRI examinations detected relevant and new lesions in 9 (69.2 %) patients which affected treatment in 8 (61.5 %) individuals. CONCLUSION:Using a protocol with a reduced specific energy absorption rate, spinal MRI examinations in patients with SCS can be considered safe. The current view that neurostimulators are a general contraindication to MR examinations has to be reconsidered in patients with new or progressive spinal symptoms