Vertebroplasty: Absence of Evidence Yields to Evidence of Absence. It Takes a Sham to Discover a Sham but how will I Get a Sham if I Need One?

"When in doubt, cut it out" is one simplified heuristic (rule of thumb) of surgery. Extension (via inductive thinking) of the observation that removing a necrotic gallbladder or correcting some other anatomic aberration causes improvement in patient outcomes to other situations has misled us before. It is simply not always that simple. While it makes sense that arthroscopic removal of scar tissue in an osteoarthritic knee will improve patients' symptoms, alas, some investigators had the courage to challenge that assumption, and reported in 2002 that when compared to sham surgery, knee arthroscopy did not benefit patients. (See http://content.nejm.org/cgi/content/abstract/347/2/81.)

In a beautiful extension of that line of critical thinking, two groups of investigators in last week's NEJM challenged the widely and ardently held assumption that vertebroplasty improves patient pain and symptom scores. (See http://content.nejm.org/cgi/content/abstract/361/6/557 ; and http://content.nejm.org/cgi/content/abstract/361/6/569 .) These two similar studies compared vertebroplasty to a sham procedure (control group) in order to control for the powerful placebo effect that accounts for part of the benefit of many medical and surgical interventions, and which is almost assuredly responsible for the reported and observed benefits of such "alternative and complementary medicines" as accupuncture.

There is no difference. In these adequately powered trials (80% power to detect a 2.5 and a 1.5 point difference on the pain scales respectively), the 95% confidence intervals for delta (the difference between the groups in pain scores) were -0.7 to +1.8 at 3 months in the first study and -0.3 to + 1.7 at 1 month in the second study. Given that the minimal clinically important difference in the pain score is considered to be 1.5 points, these two studies all but rule out a clinically significant difference between the procedure and sham. They also show that there is no statistically significant difference between the two, but the former is more important to us as clinicians given that the study is negative. And this is exactly how we should approach a negative study: by asking "does the 95% confidence interval for the observed delta include a clinically important difference?" If it does not, we can be reasonably assured that the study was adequately powered to answer the question that we as practitioners are most interested in. If it does include such a value, we must assume that for us given our judgment of clinical value, the study is not helpful and essentially underpowered. Note also that by looking at delta this way, we can determine the statistical precision (power) of the study - powerful studies will result in narrow(er) confidence intervals, and underpowered studies will result in wide(r) ones.

These results reinforce the importance of the placebo effect in medical care, and the limitations of inductive thinking in determining the efficacy of a therapy. We must be careful - things that "make sense" do not always work.

But there is a twist of irony in this saga, and something a bit concerning about this whole approach to determining the truth using studies such as these with impeccable internal validity: they lead beguillingly to the message that because the therapy is not beneficial compared to sham that it is of no use. But, very unfortunately and very importantly, that is not a clinically relevant question because we will not now adopt sham procedures as an alternative to vertebroplasty! These data will either be ignored by the true-believers of vertebroplasty, or touted by devotees of evidence based medicine as confimation that "vertebroplasty doesn't work". If we fall in the latter camp, we will give patients medical therapy that, I wager, will not have as strong a placebo effect as surgery. And thus, an immaculately conceived study such as this becomes its own bugaboo, because in achieving unassailable internal validity, it estranges its relevance to clinical practice insomuch as the placebo effect is powerful and useful and desireable. What a shame, and what a quandry from which there is no obvious escape.

If I were a patient with such a fracture (and ironically I have indeed suffered 2 vertebral fractures [oh, the pain!]), I would try to talk my surgeon into performing a sham procedure (to avoid the costs and potential side effects of the cement).....but then I would know, and would the "placebo" really work?