CLINICAL OUTCOMES Kyphon Balloon Kyphoplasty

Beall DP, Chambers MR, Thomas S, et al. Prospective and multicenter evaluation of outcomes for quality of life and activities of daily living for balloon kyphoplasty in the treatment of vertebral compression fractures: the EVOLVE trial. Neurosurgery. 2019;84:169-178.

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• Level II evidence
• Single-armed trial at 24 sites in U.S.
• 354 patients with painful vertebral compression fractures (VCFs) due to primary/secondary osteoporosis, multiple myeloma, or osteolytic metastatic tumors; single armed, prospective cohort
• Follow-up 7 days, and 1, 3, 6, and 12 months

Four co-primary endpoints: Numerical Rating Scale back pain (NRS), Oswestry Disability Index (ODI), Short Form 36-question Physical Component Summary (SF-36v2 PCS), EuroQol-5-Domain (EQ-5D) were evaluated for statistically significant improvement 3 months after kyphoplasty.

• Between baseline and 3-month follow-up, NRS improved from 8.7 to 2.7 and ODI improved from 63.4 to 27.1; SF-36 PCS was 24.2 at baseline improving to 36.6, and EQ-5D improved from 0.383 to 0.746 (p < 0.001 for each).
• Five device-/procedure-related adverse events (intraoperative asymptomatic balloon rupture, rib pain, aspiration pneumonia, new VCF 25 days post-procedure, myocardial infarction 105 days post-procedure) were reported; each resolved with proper treatment.

Single-arm study with no control comparison; 25 percent loss to follow-up at 12 months. Heterogeneity was introduced by including both osteoporotic and neoplastic fractures, but vast majority of subjects (98 percent) had osteoporosis.

Dohm M, Black CM, Dacre A, Tillman JB, Fueredi G, KAVIAR investigators. A randomized trial comparing balloon kyphoplasty and vertebroplasty for vertebral compression fractures due to osteoporosis. AJNR Am J Neuroradiol. 2014;35:2227-2236.

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• Level one evidence
• Randomized control trial (RCT) of balloon kyphoplasty (BKP) compared to vertebroplasty (VP) for patients with painful osteoporotic VCF
• 26 centers U.S. and Canada
  • N = 304 patients (190 BKP; 205 VP)
  • Study was supposed to enroll, 1234 to detect 8.7 percent difference in subsequent radiographic fractures
• Patients:
  • One to three acute, painful osteoporotic VCFs from T5-L5
  • Correlative clinical findings with edema on MR imaging
  • Uptake on radionuclide bone scans, or acute vertebral height loss within 6 months by CT, MRI, or X-ray

• Primary endpoint
  • Proportion of patients with new radiographic VCFs at 12 and 24 months (including new or any worsening index fractures)
• Secondary endpoints
  • SF-36 PCS
  • EQ-5D
  • NRS
  • ODI
  • Standing lateral spine radiographs at baseline, post-op, 3, 12, 24 months. Determined new radiographic fracture by Genant; vertebral kyphotic angulation.
  • Post-procedural CT scan to determine cement leakage

• BKP approached statistical significance for longer fracture-free survival on new clinically recognized fractures (p = 0.0596)
• BKP trended toward fewer radiographic subsequent fractures compared to VP but was not statistically significant
• 12 months: BKP had 7.8 percent fewer subsequent radiographic fractures compared to VP (p = 0.21)
• 24 months: BKP had 8.6 percent fewer subsequent radiographic fractures compared to VP (p = 0.23)
• Greater kyphotic correction at 24 months in BKP group: difference was 1.42 degrees (p = 0.036)
• Cement extravasation: BKP 73 percent; VP 82 percent; p = 0.047
• Intravascular extravasation. 28 percent BKP compared to 38 percent VP; p = 0.028
• Back pain, SF-36 PCS, Eq-5D, ODI, opioid use: Both BKP and VP had significant improvements from baseline over time but were not statistically significantly different from each other.
• BKP and VP had similar safety profile with few device-related complications. Most common adverse event (AEs) within 30 days of surgery were procedural pain (12 BKP; 9 VP), back pain (14 BKP; 28 VP) and new symptomatic fractures (9 BKP; 17 VP). Common AEs over 2 years were bronchitis (10 BKP; 10 VP), pneumonia (15 BKP; 12 VP), urinary tract infection (11 BKP; 19 VP), falls (47 BKP; 46 VP), procedure pain (1 BKP; 9 VP), arthralgia (18 BKP; 12 VP), back pain (49 BKP; 59 VP), lumbar vertebral fracture (9 BKP; 13 VP) and thoracic vertebral fracture (20 BKP; 21 VP). A few AEs, including procedural pain (3 BKP; 3 VP), back pain (2 BKP; 3 VP), new fractures (2 BKP; 2 VP), cement embolism (1 BKP; 1 VP), muscle spasm (1 BKP; 0 VP), arthralgia (1 BKP; 0 VP), bone marrow edema (0 BKP; 1 VP) and implant site extravasation (0 BKP; 1 VP) were specifically considered to be device related. Five (5) BKP AEs (constipation, procedural hypotension, hallucination, exacerbated COPD) and 5 VP AEs (hypersensitivity, mental status changes, hypoxia, respiratory failure, hematoma) were considered anesthesia or procedure related. No death was noted as device or procedure related.

Lack of patient blinding, substantial loss to follow-up and early termination (404 enrolled out of 1,234 patient enrolment goal), which resulted in lack of statistical power for the primary endpoint.

Van Meirhaeghe J, Bastian L, Boonen S, et al. A randomized trial of balloon kyphoplasty and nonsurgical management for treating acute vertebral compression fractures: vertebral body kyphosis correction and surgical parameters. Spine. 2013;38:971-983.

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• Level one evidence
• Randomized controlled trial at 21 sites in eight countries
• 300 patients with one to three vertebral compression fractures were randomized 149 BKP and 151 non-surgical management (NSM)
  • 232 patients (120 BKP; 112 NSM) were available for analyses at the 2-year follow-up
  • Nonsurgical management: Consisted of analgesics, bed rest, bracing, physiotherapy, rehabilitation programs, and walking aids according tostandard practices of participating physicians and hospitals

• This manuscript compared BKP and NSM in changes in functional, quality of life, and pain outcomes over a 2-year period. Unique measures that were evaluated in this manuscript included:
  • Timed-Up-and-Go (TUG)
  • Patient satisfaction
  • Predictors of outcome

Mean improvement across all visits through 24-months was better in BKP vs. NSM

• EQ-5D: by 0.10 points (p < 0.0001)
• VAS (NRS) by 1.29 points (p < 0.0001)
• RMDQ: by 2.39 points (p < 0.0001)
• Patient satisfaction: by 3.09 points (p < 0.0001)
• TUG: by 2.49 points (p = 0.0036)
• TUG categorized: freely mobile (> 0 to 5 10), mostly independent (> 10 to 5 20), variable mobility (> 20 to 5 30) and impaired mobility (> 30). Looking at how patients changed in these categories over time, higher rate of BKP subjects remained improved out to 6 months vs. NSM (p = 0.0013).
• Kyphotic angulation improvements at 24 months: BKP 3.13 degrees vs. NSM 0.82 (p = 0.003)
• The BKP group had mean post-op anterior gain of 10 percent and mid-vertebral change in height of 8.3 percent = an estimated 27 percent and 25 percent of lost height restored in BKP group, respectively.
• At 24 months, anterior measurement changes were BKP 6.7 percent vs. NSM 1.1 percent (p = 0.022); and medial measurements were BKP 5.9 percent improvement and NSM 1.9 percent worsening (p < 0.001).
• Correlation between kyphotic angulation correction and clinical outcome: BKP patients with highest kyphotic angulation correction had higher PCS improvements (13.4 points vs. subgroup having the lowest correction of angulation 7.4 points) p = 0.0146. Patients with highest PCS improvement had better kyphosis correction (5.18 degrees) compared with the subgroup having the lowest amount of PCS improvement (1.98 degrees) p = 0.0272. These analyses were not statistically significant for the patients in the NSM group.
• Upper and lower quarts for VAS backpain, EQ-5D QOL and Roland-Morris disability were analyzed. In the BKP group, angulation correction was statistically significantly higher in the upper quarts for each of these parameters except for RMDQ.
• Predictive analyses: fewer baseline fractures (p = 0.0003), younger fracture age (0.0548), and BKP treatment group (0.0040) predicted better SF-36 PCS scores.
• In BKP sub-group, fewer baseline fractures (p = 0.0064), baseline pain (0.0709), and change in kyphotic angulation (0.0727) were best predictors.
• In NSM, fewer fractures (p = 0.0444), younger fracture age (0.0446) were best predictors.

• The FREE study was non-blinded; knowledge of treatment assignment may have influenced patient responses or radiologist assessments.
• Nonsurgical care was not standardized across treatment centers but represents common practice.
• The analyses of clinical outcomes and radiographical results (kyphotic angulation correction) suggest a link but were exploratory in nature and less predictive than other variables such as baseline prevalent fracture; more studies are required where the study design is appropriately focused to confirm this hypothesis.

Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncology. 2011;12:225-235.

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• Level one evidence
• Prospective, randomized controlled trial at 22 sites (U.S., Canada, Europe, Australia)
• N = 134 patients (n = 70 BKP; n = 64 NSM)
• Cross-over allowed at 1 month for NSM group
• Nonsurgical management: All patients could receive analgesics, bed rest, bracing, physiotherapy, rehabilitation programmes, walking aids, according to the medical dictionary for regulatory activities.

• Primary endpoint: Back specific physical functioning: RMDQ at 1 month
• Secondary endpoints:
  • Quality of life: SF-36
  • Functional impairment: Karnofsky Performance Scale (KPS)
  • Back pain: NRS
  • Analgesics used to treat back pain
  • Reduced activity days caused by back pain

• At 1 month (as randomized)
• RMDQ
• BKP: baseline 17.6 points to 9.1 at 1 month (within group change p < 0.0001); NSM: baseline 18.2 points to 18 at 1 month (within group change p = 0.83).
• Study Primary endpoint: Between-group differences of -8.4 points (95 percent CI -7.6 to -9.2) at 1 month (p < 0.0001).
• Significantly more BKP (81 percent) had clinical improvement (2-point MCID) compared with NSM (28 percent) (p < 0.0001).
• BKP patients had greater improvement in KPS scores (15.3 points; 95 percent CI 13.5-17.1) compared to NSM (p < 0.0001). Similarly, there were more subjects with KPS scores ≥ 70 (clinically meaningful threshold) at 1 month: BKP 75 percent NSM 39 percent.
• SF-36 at 1 month: greater improvement with BKP (9.4 point change) vs. NSM (1-point change); p < 0.0001.
• The number of patients with adverse events was similar between BKP and NSM; for example, most common adverse events were back pain (4/70 BKP and 5/64 NSM control) and subsequent symptomatic VCF (2 BKP and 3 NSM).
• The number of patients with radiographic subsequent fractures were not different between BKP (19.4 percent) and NSM (17.0 percent); p = 0.76.
• BKP related serious adverse events: one patient experienced an intraoperative non-Q-wave myocardial infarction with intermittent atrial fibrillation both attributed to anesthesia and resolved; one patient with cement leakage to adjacent disc had an adjacent fracture occur 1 day after the procedure that was considered device-related.
• 12 months (as treated analysis): Crossover after 1 month of randomized treatment: 38 NSM patients at mean 47± 45.4 days.
• Improvements seen at 1 month post-BKP were similar in patients randomized to immediate BKP as compared to those who chose to crossover. In general, in both the original BKP group and the crossover BKP group, 1-month outcomes were maintained through the final 12-month assessment (NRS Pain Score, RDQ ad SF-36 PCS).
• Beyond the 1-month randomization period, the original BKP group had no additional device-related serious medical complications.
• For crossover subjects, BKP-related serious adverse events included one airway complication related to anesthesia (resolved) and 1 subject with a subsequent fracture 13 days post-procedure considered possibly device-related.

• Randomization of treatment was not blinded and lasted for only 1 month. After the first month, patients were allowed to cross over from NSM to BKP, creating a non-randomized population for the long-term analysis.
• Sample size was adjusted lower, which was not according to pre-specified plan.

Boonen S, Van Meirhaeghe J, Bastian L, et al. Balloon kyphoplasty for the treatment of acute vertebral compression fractures: 2-year results from a randomized trial. J Bone Miner Res. 2011;26:1627-1637.

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• Level one evidence
• Randomized controlled trial (RCT) at 21 sites in eight countries
• 300 patients with one to three vertebral compression fractures (VCFs) due to primary/secondary osteoporosis, multiple myeloma, or osteolytic metastatic tumors
• Patients randomized BKP (n = 149) and non-surgical management (NSM; n = 151)
• Follow-up at 1, 3, 6, 12, 24 months (this publication is the 2-year follow-up)
• Non surgical management : Patients received analgesics, bed rest, bracing, physiotherapy, rehabilitation programs, and walking aids according to standard practices of participating physicians and hospitals, and all patients were referred for treatment with calcium and vitamin D supplements and antiresorptive or anabolic agents

• This analysis compared BKP and NSM in changes between baseline and 24 months in Short Form 36 physical component score (SF-36 PCS), quality of life (EQ-5D), back function and mobility (Roland Morris Disability Index; RMDQ), back pain (VAS), and adverse events.
• This manuscript also evaluated subsequent fracture rates.

• SF-36 PCS. BKP group had significant improvements compared to NSM at the 6-month follow- up (p = 0.001); but these differences were no longer statistically significant at 12- and 24-month follow-up.
• EQ-5D: BKP group had significant improvements compared to NSM at 6 months (p = 0.0009); 12-months (p = 0.006), and 24-months (p = 0.040).
• RMDQ: BKP group had significant improvements compared to NSM at 6 months (p < 0.0001) and 12 months (p < 0.0001); but not at 24 months (p = 0.059).
• Reduced days of activity: BKP 6.9 days compared to 10.4 days of restricted activity at 1 month (p < 0.0001).
• BKP group had significant improvements compared to NSM at 6 months (p = 0.0008) and 12 months (p = 0.006); but not at 24 months (p = 0.12).
• Back pain (VAS): BKP group had significant improvements compared to NSM at 6 months; (p < 0.0001) 12 months (p = 0.001), and 24 months (p = 0.006).
• No statistical difference in the rate of new radiographic subsequent fractures between the two groups at 24 months: 47.5 percent BKP vs. 44.1 percent NSM; p = 0.68.
• No statistically significant difference in the rate of adjacent radiographic fractures at 24 months: BKP 23.7 percent vs. 16.7 percent; p = 0.24.
• Pain medications:
  • 12 months: BKP 51.7 percent; NSM 68.3 percent; p = 0.013
  • 24 months: BKP 24.6 percent; NSM 21.9 percent; p = 0.74
• Opioid:
  • 6 months: BKP 29.8 percent; NSM 42.9 percent; p = 0.042
  • 12 months: BKP 28 percent; NSM 33.7 percent; p = 0.38
  • 24 months: BKP 8.8 percent; NSM 9.5 percent; p = 1.0
• Patient satisfaction:
  • BKP patients were more satisfied (treatment effect 3.09 points, 95 percent CI 2.26-3.92, p < 0.0001).
  • Difference was significant at ALL time points, including 24 months (24 months = 2.31 points difference, 95 percent CI 1.19-3.43, p < 0.0001).
• There were no differences in the rates of adverse events or serious adverse events; three patients with four BKP procedure/device-related serious adverse events were reported (spondylitis, an anterior cement migration, urinary tract infection, subcutaneous hematoma). No device- or procedure-related myocardial infarctions, pulmonary embolisms, neurological injuries, or deaths.

• The FREE study was non-blinded; knowledge of treatment assignment may have influenced patient responses, or radiologist assessments.
• Nonsurgical care was not standardized across treatment centers but represents common practice.