undergo either vertebroplasty or a simulated sham procedure, which included infiltration of anesthetic into the periosteum of the posterior lamina. Th

Transcription

1 Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Mark Otto Baerlocher, MD Peter L. Munk, MD David M. Liu, MD George Tomlinson, PhD Maziar Badii, MD Stephen T. Kee, MD Chris T. Loh, MD Brian W. Hardy, MD Kieran J. Murphy, MD Published online /radiol Radiology 2010; 255: From the Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada (M.O.B., K.J.M.); Department of Radiology, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada (P.L.M., D.M.L.); Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada (G.T.); Division of Rheumatology, University of British Columbia, Vancouver, British Columbia, Canada (M.B.); Angio/ Interventional Section, UCLA Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, Calif (D.M.L., S.T.K., C.T.L.); and Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada (B.W.H.). Received February 23, 2010; revision requested February 26; fi nal revision received March 2; fi nal version accepted March 8. Address correspondence to M.O.B., 13 Marshview Dr, Sackville, NB, Canada E4L 3B2 ( mark.baerlocher@utoronto.ca ). P.L.M. is on the Speaker s Bureau for Cook Medical (Bloomington, Ind), and K.J.M. has intellectual property concerning vertebroplasty devices and has a royalty relationship with Cook (Bloomington, Ind), which makes vertebroplasty devices, and stock options in Vexim (Toulouse, France), Dfi ne (San Jose, Calif), and Spineology (St Paul, Minn), which make spine devices. See also the article by Kallmes in this issue. Supplemental material: /suppl/doi: /radiol /-/dc1 q RSNA, 2010 Clinical Utility of Vertebroplasty: Need for Better Evidence 1 Vertebral compression fractures (VCFs) are a common cause of low back pain that may lead to serious clinical consequences, including neurologic compromise, permanent disability, spinal deformity, and difficulty in breathing, if untreated ( 1 ). Vertebroplasty is a minimally invasive procedure performed for the treatment of both acute and chronic severe back pain associated with VCFs. The procedure involves injection of cement into the collapsed vertebral body and may be used to treat a number of underlying causes, including osteoporosis, osteonecrosis, painful hemangiomas, and malignancy (ie, pathologic fractures). Vertebroplasty has been well documented to provide significant pain relief to patients in whom conservative therapy with bed rest, analgesics, external back bracing, and physical therapy and/ or exercise has failed, which has led to its formal endorsement by multiple societies ( 2 ). In the United States alone, it is estimated that up to patients undergo the vertebroplasty procedure annually ( 3 ). Until recently, most of the published data on vertebroplasty have been in its favor, both in the treatment of painful osteoporotic fractures and in the treatment of painful pathologic fractures ( 4 ). Benefits derived from vertebroplasty include pain relief, increased mobility, and increased function. Depending on the trial, 60% 100% of patients benefited from significant pain relief, 34% 91% used less analgesic medication, and 29% 100% enjoyed greater mobility ( 5 14 ). A recent exhaustive, systematic review by McGirt et al ( 4 ) concluded that there is level I evidence that vertebroplasty results in superior pain control within the first 2 weeks of intervention compared with optimal medical management for osteoporotic vertebroplasty compression fractures, and there is level II III evidence that vertebroplasty results in less analgesia use, less disability, and greater improvement in general health when compared with optimal medical management within the first 3 months after intervention. Vertebroplasty is indicated in cases of localized pain that impedes function and activities of daily living, where medical treatment either has failed or is contraindicated. Absolute or potential contraindications include osteomyelitis, allergy to the cement agent or to contrast medium, pregnancy, and uncorrectable coagulopathy ( 9,15,16 ). Two Recent Randomized Controlled Trials Investigators in two recently published randomized controlled trials ( 17,18 ) concluded that there is no benefit to the procedure over a sham placebo procedure involving the injection of local anesthetic into the area adjacent to the fracture. In the study by Buchbinder et al ( 17 ), 78 patients with one or two painful osteoporotic VCFs were randomized to receiver either vertebroplasty treatment or a designated sham procedure, which included infiltration of anesthetic into the pedicular periosteum. The primary measured outcome was overall pain at 3 months. Despite significant reductions in overall pain in both groups, there was no significant advantage of vertebroplasty over the sham procedure (mean, [standard deviation] and for the vertebroplasty and control groups, respectively). In the study by Kallmes et al ( 18 ), 131 patients with one to three painful osteoporotic VCFs were randomized to Discuss this article online at REVIEWS AND COMMENTARY n CONTROVERSIES Radiology: Volume 255: Number 3 June 2010 n radiology.rsna.org 669

2 undergo either vertebroplasty or a simulated sham procedure, which included infiltration of anesthetic into the periosteum of the posterior lamina. The primary outcomes measured were scores on the modified Roland-Morris Disability Questionnaire (RDQ) and average pain intensity during the preceding 24 hours at 1 month. Treatment group crossover was permitted at 1 month. At 1 month, there was no significant difference between the two groups in either the RDQ score (difference, 0.7; P =.49) or the pain rating (0.7, P =.19). At 3 months, there was a trend of clinically important decreased pain (30%) among the vertebroplasty group (64% vs 48% [sham group], P =.06). Both analyses are fundamentally flawed in several important respects. Unfortunately, the results of these analyses have already begun to lead to somewhat of a backlash against the procedure in both the lay national and international media ( 19,20 ) and, in particular, may jeopardize funding for payment of these clinical services. We are concerned that potential misinterpretation of the data presented in both articles may result in unwarranted conclusions by the noncritical reader. We offer a critical analysis of the methods and outcomes of the two studies in the hopes of promoting properly designed vertebroplasty trials. Study Flaws There are three significant flaws with both studies: (a) power, sample size, and interpretation of a negative result; (b) recruitment; and (c) generalizability. A fourth issue we will briefly mention concerns what constitutes a true placebo. In both analyses, there was a trend that supported treatment benefit of vertebroplasty; however, in both, the P value was greater than.05. In the study of Buchbinder et al ( 17 ), to achieve a power of 80%, P =.05, with intermediate effect size (0.3 as defined by Cohen [ 21] ), approximately 350 patients would be required. The study included 78 patients. In the study by Kallmes et al ( 18 ), the authors note that an initial target of 250 patients was determined on the basis of a pretrial power analysis; after difficulty recruiting patients, the authors changed the accrual target to 130 patients in mid trial. It is certainly not unreasonable for research trials to be terminated prior to reaching their patient accrual goal; however, that occurs generally in situations where interim data analyses demonstrate it to be either unethical or pointless to continue, not simply because patient recruitment was too onerous. In addition, the study by Kallmes et al ( 18 ) offered crossover following the initial 1-month period. We would question whether 1-month outcomes were set to represent the primary outcomes so that recruitment could be boosted by offering crossover to subjects after 1 month (the main outcomes reported appear to all be at 1 month). Because the study by Kallmes and colleagues (18) had an asymmetric and high crossover rate from control to the vertebroplasty groups following this initial 1-month period (43% versus 12%; P,.001), comparison of outcomes at 3 months is difficult: Any true benefit of vertebroplasty at 3-month follow-up may be hidden, as intention-to-treat analysis was used. Perhaps without knowing it, the authors used what has been referred to as an optional crossover design ( 22 ). This design has been advocated in cases in which subjective impressions about success or failure of a treatment are crucial and essentially allows trial randomized participants the option of crossing over following phase I of a treatment. The idea is that more patients will cross over and end up in the treatment most effective if one treatment truly is superior; if the treatments are equivalent, crossover rates will essentially be the same. In the study by Kallmes et al (18), the asymmetric crossover may indicate either unblinding or a true benefit of treatment (in the former case, a significant flaw; in the latter, a finding that challenges the validity of the authors conclusions). Trials that fail to demonstrate significant differences between treatments need to be interpreted carefully ( 23 ). A failure to find a significant difference does not mean that there is no difference. After a so-called negative trial, a reasonable question is thus: What is the chance that an important treatment effect exists? This is different from a study s type II error rate (1 2 power), which, informally, is the chance was that a study would not yield a significant result if there was an important treatment effect. The 95% confidence interval (CI) gives one way of answering this question; if an important effect lies in the interval, then it is consistent with the observed data. In these two studies, the minimally clinical importance difference (MCID) values for several outcomes lie within 95% CIs for treatment effects, so important effects for these outcomes are consistent with the data. When the MCID value lies toward the end of the CI, a vague statement can be made about large effects being unlikely. For example, the 95% CI for improvement in pain at 6 months extends from 0.6 to 1.9 in the study by Buchbinder et al (17). Supposing that the MCID is 1.5, we may think that because 1.5 is in the upper part of the CI, the data do not lend much support to a treatment effect that large. However, to us, this semiquantitative judgment seems to be a poor answer to an important question. To obtain a better answer, a Bayesian inference must be applied. It is beyond the scope of this article to explain Bayesian inference; however, we can direct the interested reader to a recent article ( 24 ) in which the researchers used methods similar to ours to reinterpret the results of 39 positive and 49 negative trials. We will, however, use an analogy to the diagnostic test to illustrate one important distinction between a classical statistical analysis and a Bayesian analysis. After a clinician has the result of a diagnostic test, he or she wants to know the probability that the patient has the disease. It is of no use to know how likely the result was, given that the patient did not have the disease. Likewise, after observing a particular result in a clinical trial, it is natural to ask, What is the probability that the treatment is effective? Before learning about classical statistical inference, no 670 radiology.rsna.org n Radiology: Volume 255: Number 3 June 2010

3 one would ask, What are the chances of obtaining data more extreme than my data if the treatment is not effective? By using some simple calculations that are based on the reported data (Appendix E1 [online]), a Bayesian analysis can answer the clinically relevant question, Given the study finding, what is the chance that a treatment effect exists? Below, we interpret this question in two ways: (a) What is probability that the treatment effect exceeds the MCID? (b) What is the probability that the treatment is effective at all? The Table shows these two probabilities for the outcomes for which the authors report MCID values and for perceived pain. An MCID is not provided for the relative risk of change in perceived pain, so we chose a value of relative risk of 1.5. In column 1, although there is little chance of a large true effect on night pain or RDQ in the study of Buchbinder et al (17), for example, the results do leave open the possibility of substantial benefit on several outcomes. In the Buchbinder study, there is a 17% probability that EQ5D scores improve by more than the MCID and a 24% probability that the relative risk for pain reduction is larger than 1.5. Column 2 shows that, for pain and risk of pain in the Buchbinder et al study and pain and RDQ in the Kallmes et al study (18), the probabilities of any Probabilities of Treatment Effects Being Larger than MCID Outcome Measure and Study beneficial effect range between 72% and 92%. Although Buchbinder et al (17) and Kallmes et al (18) did not find strong evidence of benefit for any of their outcomes, the relatively small sample sizes of these two studies leave a fair amount of statistical uncertainty about the true effect of vertebroplasty and, especially in light of extensive evidence in favor of the procedure from nonrandomized studies, the results must be regarded as inconclusive. If we were to perform one-sided significance tests of the hypothesis that the true treatment effect was equal to or larger than the MCID, we would not reject this hypothesis for pain, AQOL, EQ5D, and risk of pain in the Buchbinder et al study (17) and pain and RDQ (MCID = 2) in the Kallmes et al (18) study. Both Bayesian and frequentist arguments lead to the same conclusion: We cannot rule out the possibility that there are important benefits with vertebroplasty. The second criticism is in regard to patient recruitment, specifically the preprocedural pain scores as measured by using the Visual Analog Scale. We found that patients in a greater degree of pain before the procedure tend to exhibit a greater benefit from the procedure ( 25 ). The preprocedural pain scores measured by using the Visual Analog Scale were relatively low in both Probability of Effect Larger than MCID (%) 3-mo outcomes in study by Buchbinder et al (17) Pain 8 83 Night pain 1 56 AQOL RDQ; MCID = 3, 1 18 RDQ; MCID = EQ5D Risk of pain mo outcomes in study by Kallmes et al (18) Pain 6 92 RDQ;MCID = RDQ; MCID = Note. AQOL = Assessment of Quality of Life, EQ5D = EuroQol 5 Dimensions. Probability of Any Benefi cial Effect (%) studies, presumably as patients with a greater degree of morbidity would be less likely to enter such a trial and risk randomization to the sham procedure. In the study by Buchbinder et al ( 17 ), for example, 248 of 468 patients were ineligible; of the remaining 220, only 78 (35%) agreed to participate (versus 30% in the Investigational Vertebroplasty Efficacy and Safety Trial, or INVEST). Although this rate is similar to the recruitment rate in other major vertebroplasty trials, and we certainly can appreciate the difficulty in trial recruitment, there remains substantial room for bias. By including a substantial number of patients with a lesser degree of preprocedural pain, the effect size would be diminished and, therefore, the sample size required to show significance from the control would have to be increased. One may argue that an increased benefit may simply be caused by a regression-toward-the-mean phenomenon. This argument seems rather convenient and has no greater validity applied in this case as to any other trial in which an attempt is made to search for a severity-related response. Third, previous evidence has suggested that the specific type or characteristics of the compression fracture may influence outcomes. For example, we found that patients with compression fractures that exhibit a gas-filled cleft are more likely to draw benefit from vertebroplasty. Researchers in previous studies have both supported our experience ( 26 ) and found contrary results: Trout et al ( 27 ) found that these fractures were associated with an increased likelihood of subsequent adjacent fractures after vertebroplasty. Other workers ( 28 ) demonstrated that patients with fractures containing clefts are more likely to enjoy a greater reduction in kyphosis, as well as reduced likelihood of cement leakage, after vertebroplasty. Patients with pathologic fractures, who were excluded from both trials, similarly tend to exhibit responses that are different from the responses of patients with osteoporotic fractures. It has been our experience, as well as that of others, that patients with pathologic fractures typically complain of much greater pain Radiology: Volume 255: Number 3 June 2010 n radiology.rsna.org 671

4 before the procedure than do patients with osteoporotic fractures, and they demonstrate much greater reduction in pain after the procedure ( 29,30 ). Other questions also remain: For example, one may ask whether it is more appropriate for patients with compression fractures to be treated immediately following onset of pain, as opposed to undergoing treatment months later after medical treatment has failed. The researchers in both of the recent studies published in the New England Journal of Medicine excluded pathologic fractures, and neither study was large enough to allow for meaningful subanalyses. It is clear that there are many subtleties that must be worked out. To do so, either much larger, greater-powered studies are necessary and/or studies that target specific fracture types or causes (eg, pathologic) are needed. We acknowledge, however, the risk of mining the same data. Finally, we question whether the placebo was a true placebo in the trial by Kallmes et al (18), as bupivacaine (a long-acting anesthetic) was administered in the sham group: We wonder how a similar sham group would compare with a matched group treated only with conservative therapy. Patients in whom vertebroplasty fails to resolve or significantly improve pain are often subsequently treated with medial branch block at our institutions, often with great success (Peter L. Munk, MD [University of British Columbia, Vancouver, British Columbia, Canada], unpublished data, 2009). Indeed, findings in previous work by Lehman et al ( 31 ) in a small group of patients with dementia (and therefore assumed decreased potential expectationrelated placebo effect) suggested that the placebo effect does not explain the entire benefit of vertebroplasty. Impact on Vertebroplasty Support Because the impact of the results of the studies by Buchbinder et al (17) and Kallmes et al (18), published in the New England Journal of Medicine, may be enormous, misinterpretation of these results could lead to tens of thousands of patients being denied a valuable procedure that the great bulk of studies to date have validated as a safe and effective therapy ( 5 13,32,33 ). Furthermore, multiple medical societies, including the Society of Interventional Radiology, American Society of Interventional and Therapeutic Neuroradiology, American Association of Neurologic Surgeons/ Congress of Neurologic Surgeons, and American Society of Spine Radiology ( 2 ), have previously supported and endorsed cement augmentation. Already, there have been a number of high-profile stories in the lay media, including the Wall Street Journal with the headline Spine Surgery Found No Better than Placebo ( 20 ) and CBS news with the headline Unnecessary Procedures ( 19 ). In our personal combined experiences treating more than 2000 patients, we have observed tremendous benefit in performing vertebroplasty, both in terms of improvement in quality of life and rapid recovery and decreased days of hospitalization for patients debilitated owing to intractable pain and profound muscle spasm, including those with oncologic fractures patients who were clearly not addressed in either study. Numerous other experts across the world have begun to submit criticisms of the studies, which follow those detailed above ( 3,34 ). Neither of these studies should lead readers to the overly simplistic conclusion that vertebroplasty is an unnecessary procedure, as some widely viewed media have unfortunately and erroneously implied ( 19 ). In fact, even one of the authors of the Kallmes et al (18) trial, Dr Jeffrey Jarvik, apparently makes this mistake in an interview with the Wall Street Journal : Vertebroplasty should not be done any longer, unless it s in the setting of a study ( 20 ). Future Vertebroplasty Studies Both the study by Buchbinder et al (17) and that by Kallmes et al (18) should be used as a valuable starting point from which to elucidate which subsets of patients are likely to derive the greatest benefit from the procedure. Specialty society endorsement and personal experience should not in and of themselves trump well-designed trials, particularly randomized trials; however, with the noted substantial flaws (acknowledged by an author of the trial by Kallmes et al [ 18 ] in an article [ 35 ]), and the volume of other studies (albeit perhaps less rigorous) in favor of vertebroplasty to date, including a previous prospective randomized controlled trial ( 36 ), we urge caution in assuming that these two studies on their own decisively invalidate the majority of previous work. As mentioned above, the specific characteristics and etiology of fracture may have important implications. For example, in our experience, patients with high levels of preprocedural pain, fractures containing gas-filled clefts, and pathologic fractures may be high responders to vertebroplasty. Greaterpowered randomized controlled trials and/or more targeted trials that include a clinical assessment component are necessary at this point to demonstrate whether this is the case. One challenge will be recruiting patients with a high preprocedural pain score who would be willing to be risk randomized (and therefore receive potential placebo treatment), a situation to some degree reminiscent of a previous tongue-in-cheek reflection of the limitations of randomized design ( 37 ). As we mentioned above, perhaps the most appropriate conclusion that may be drawn from the two studies is that vertebroplasty is not indicated for all patients, although this is a far stretch from concluding outright that vertebroplasty is not a useful procedure, as some media seem to imply. Now that a substantial degree of skepticism exists in regard to the benefit of vertebroplasty, future trials will hopefully have much greater success in physician and subsequent patient recruitment. We encourage those who perform vertebroplasty to apply for enrollment into a current or future vertebroplasty trial and to actively recruit patients. Vertebroplasty for Palliation of Malignant Compression Fractures As an aside, it should also be made clear that the controversy surrounds 672 radiology.rsna.org n Radiology: Volume 255: Number 3 June 2010

5 vertebroplasty performed specifically for painful osteoporotic compression fractures. There is a substantial amount of evidence supporting its use for palliation of neoplastic compression fractures, and the results of the two recently published studies by Buchbinder et al (17) and Kallmes et al (18) do not have an effect on this factor, as both excluded pathologic compression fractures. On the other hand, formal blinded randomized controlled trials for examining this benefit remain required. Outcomes-based Research in Interventional Radiology Given the potential for interventional radiologic procedures to drastically decrease waiting times, health care costs, complication rates, and time to recovery and to increase patient satisfaction, both by replacing alternative surgical treatments or by offering treatments for diseases that were previously inoperable, much more attention, funding, and resource support for outcomes-based research in the field is necessary. The studies by Buchbinder et al ( 17 ) and Kallmes et al ( 18 ) are precisely what are in order; however, they are only the first steps in establishing study designs that address the practical aspects of real-world scenarios, as opposed to creating an artificial population that may conveniently fit within a study design. Certainly, they are by no means the final word on vertebroplasty. Although we understand the hierarchy of research trials, with the double-blinded randomized controlled trial as the reference standard, we also understand that a given treatment may have a differential effect that is based on disease severity, etiology, and specific characteristics. Although we understand the risks of doggedly pursuing subanalyses and data dredging, to cease from performing subsequent more targeted studies and further investigation would be a great disservice to hundreds of thousands of future patients who may benefit from a procedure that the results of most other trials have supported. Considerable, and the bulk of, evidence, including findings from a previous randomized controlled trial ( 36 ), remains in favor of vertebroplasty for painful osteoporotic compression fractures. Indeed, the early results of the VERTOS II trial, a randomizedcontrolled trial much larger than either the study by Kallmes et al or that by Buchbinder et al, that involved 202 patients show a very positive and costeffective treatment effect of vertebroplasty over conservative therapy ( 38,39 ). We stress that the reader should not assume the authors results to be generalizable to all patients with back pain secondary to compression fracture, and we further hope that we can now begin to elucidate more precisely whether and which subsets of patients do derive a clinically significant benefit and the appropriate timing of intervention. The studies by Kallmes et al ( 18 ) and Buchbinder et al ( 17 ) should be viewed as a clear challenge and wake-up call to the interventional radiology community to step up their involvement in high-quality research trials, including, though not limited to, those examining vertebroplasty. The difficulty in patient recruitment and the tremendous effort required by the authors of both trials speak clearly to the need for greater involvement and participation by the broader scientific interventional radiology community. With the rapid innovation of treatments within the broad domain of interventional radiology, it can become quite difficult for high-quality research and, in particular, outcomes trials to keep pace. However, it is clearly necessary in the current era of evidencebased medicine, with increasing scrutiny of allocated health care dollars, to set a very high bar. There is no reason that interventional radiology cannot achieve this objective. References 1. Verlaan JJ, Oner FC, Dhert WJ. Anterior spinal column augmentation with injectable bone cements. Biomaterials 2006 ; 27 ( 3 ): Jensen ME, McGraw JK, Cardella JF, Hirsch JA. Position statement on percutaneous vertebral augmentation: a consensus statement developed by the American Society of Interventional and Therapeutic Neuroradiology, Society of Interventional Radiology, American Association of Neurological Surgeons/Congress of Neurological Surgeons, and American Society of Spine Radiology. J Vasc Interv Radiol 2007 ; 18 ( 3 ): Brice J. 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Published October 31, Accessed March 23, Klazen CA, Lohle PN, de Vries J, et al. Percutaneous vertebroplasty versus conservative therapy in patients with an acute osteoporotic vertebral compression fracture:vertos II a randomized controlled trial [abstr]. J Vasc Interv Radiol 2010 ; 21 ( 2 suppl ): S6 S radiology.rsna.org n Radiology: Volume 255: Number 3 June 2010