Number Needed to Treat with Vertebral Augmentation to Save a Life

DISCUSSION

There is a discordance between the findings of 3 sham-controlled trials of vertebroplasty and the mortality advantage suggested by claims-based studies. There are several possible reasons for this divergence. First, NSM is not risk-free therapy.¹⁶ The combination of analgesic therapy with a period of bed rest and limitation of daily activities can be counterproductive in the geriatric population. Moreover, NSM has long included opioid medications, which are increasingly understood to be problematic in this population.¹⁷ The nonsurgical arm in the VAPOUR trial had more significant complications than the vertebroplasty cohort, including paralysis related to vertebral body collapse in 2 patients several weeks after enrollment in the trial.⁸ It has proved difficult to design a methodologically sound trial that compares vertebral augmentation against a viable alternative while still avoiding the active placebo effect. While the impact of a placebo (and nocebo) is real in pain trials, it is difficult to replicate or harness these positive effects in routine clinical practice.¹⁸ Furthermore, the sham trials that showed a robust placebo response used needle docking in the periosteum and periosteal injection of local anesthetic, a technique that is known to produce pain relief, as opposed to the VAPOUR trial, which used a subcutaneous injection of local anesthetic.

In the 2010 VERTOS II trial, an open-label comparison of vertebroplasty and nonsurgical management, the positive clinical outcomes observed in those who had vertebroplasty were numerous and statistically robust.³ The 2 most recent sham-controlled blinded studies, VERTOS IV⁹ and VAPOUR, yielded different results regarding pain outcomes. This difference might, in part, relate to the design of the sham procedure, in particular the use of an active control (periosteal numbing) in VERTOS IV compared with a truer sham (subcutaneous numbing) in VAPOUR, because the amount of pain decrease seen immediately after the sham in VERTOS IV was a dramatic 3.1 point reduction on the numeric rating scale compared with the 1.8 point decrease seen in the VAPOUR trial. Understanding the potential for a control to have a treatment effect is critical for interpreting pain trials.¹⁹

Vertebroplasty practitioners, and thus trials of vertebroplasty, have focused on palliation of pain and improvement in functional status. In both VAPOUR and VERTOS IV, serial follow-up studies for the long term have demonstrated that augmented vertebral bodies preserve height more readily than those that are not augmented, and collapsed vertebral bodies have resulted in severe adverse events with loss of neurologic function. The preservation of sagittal alignment and vertebral body height also has intuitive benefits that perhaps contribute to the observed mortality advantage. The elevated risk of mortality for older patients with hyperkyphotic posture, specifically due to atherosclerosis, has been reported in a prospective study of >1300 patients.²⁰

Claims-based data have tended to demonstrate relative mortality advantages of kyphoplasty over vertebroplasty. While no blinded trial of kyphoplasty exists, primarily due to the ethical challenges of such a trial along with the difficulty in adequately designing a sham procedure, the findings of the 2009 vertebroplasty trials also ultimately cast some doubt on kyphoplasty.⁶ Ong et al⁷ noted a 55% mortality advantage of kyphoplasty over nonsurgical management at 1 year. Given the relatively low 1-year mortality event rates, this equates conservatively to an NNT of <15 to save a life at 1 year using balloon kyphoplasty rather than nonsurgical management protocols. The precise reason for this notable difference in NNT between kyphoplasty and vertebroplasty when each were compared with NSM is unclear. Recent studies have demonstrated the benefit of cementation in the preservation of height, and it could be conjectured that balloon expansion leads to better sagittal reconstruction. Confounding factors may be involved in this difference in benefit. Most notably, patients with severe comorbidities and anesthetic risk may be offered vertebroplasty over kyphoplasty; hence, a difference in outcome may be attributed to underlying medical conditions.

The original use of NNT was an epidemiologic measure designed to present data in which 2 different treatments are compared with respect to incidence rates of an unfavorable event.²¹ In practice, it facilitates understanding the clinical significance of an intervention. Although the NNT was, at first, designed to be used to indicate treatment impact in randomized controlled trials, it has also been applied to observational studies. In the case of vertebral augmentation, the very salient unfavorable event is death as demonstrated in the single largest claims-based study of VCFs.⁷

To put these numbers into practical terms, we can make comparisons with known interventions. The European Cooperative Acute Stroke Study III (ECASS-III) trial studied the use of IV-tPA administered from 3 to 4.5 hours following ischemic stroke. It was found that 15 people with acute stroke symptoms needed to be treated to achieve a single favorable outcome.²² The US Preventive Services Task Force (USPSTF) trial, pooling data from 15 trials with >70,000 patients at low risk for cardiovascular disease, found that 0.4% fewer patients taking a statin died than patients taking a placebo. This equated to an NNT of 250.²³ In another study, for those taking aspirin for 1 year to prevent a first heart attack or stroke, a cardiovascular event was prevented for 1 person in a patient population of 1667, compared with 1 in 3000 for stroke.²⁴ Each of these interventions are more favorable than the use of stents for coronary artery disease, of which studies have shown that there is no number one can treat in 5 years of follow-up to achieve any benefit.²⁵

Following the publication of the 2009 sham trials of vertebroplasty, the controversy and debate were so substantial that opportunities for learning from their findings were lost. As Firanescu et al⁹ argued, clinical care pathways that focus on improvement to NSM, moving it away from the scourge of high-dose opioid anesthesia, should be considered.²⁶ The positive outcomes demonstrated in the sham-controlled groups could indicate the potential for open-label periosteal numbing and/or medial branch blocks to be used as treatment in patients thought to be at low risk of subsequent vertebral body collapse. Further study should address the risks of vertebral body collapse and the importance of preserving vertebral body height, with future studies including it as a prespecified end point.

Using large claims-based datasets inherently equates to a heterogeneous population being analyzed retrospectively. Ong et al⁷ used propensity score matching to best account for patient covariates and reduce the bias of confounding variables. Recent advances in vertebral augmentation practices have led to discussion of the suitability of particular augmentation procedures for specific patient subgroups (eg, traumatic fractures, neoplastic fractures, patients with significant comorbidities).²⁷ Thus, there is scope for future research to analyze the utility of different techniques in different subgroups on the basis of their unique clinical conditions.²⁸ Despite these new considerations coming into focus in the discussion of vertebral augmentation, there still remains debate regarding the utility of augmentation over nonoperative management.²⁹ Thus, the low NNT to save a life when offering augmentation is an important consideration in today’s evidentiary landscape.