By Dr. Geoffrey Modest
There have been several concerning issues and lessons that I have learned in the process of doing these blogs over the past several years (I am sending out this email/blog as a follow-up to some of the methodological issues and perhaps incorrect assumptions inherent in many clinical studies and their application to actual patients, as noted in the recent blog on placebos. See http://blogs.bmj.com/bmjebmspotlight/2016/11/14/primary-care-corner-with-geoffrey-modest-md-benefits-of-placebo-for-low-back-pain-and-some-random-thoughts/
- There is huge variability in the actual utility of meta-analyses in making clinical decisions. these analyses are mathematical concoctions which try to combine different studies with usually very different people (different inclusion/exclusion criteria, people with different levels/types of comorbidites, different ages, different ethnicities, often different doses of the med being assessed, even somewhat different outcomes measured). And the meta-analyses themselves have different inclusion criteria (minimum number of people in a study that they include, the authors’ assessment of the quality of the study). And they use different statistical analyses (e.g. some do propensity score matching as a means to control mathematically for different patient baseline characteristics; or they may use different basic statistical analyses). Also, in some cases the meta-analysis is overwhelmed by a single very large study (i.e., a meta-analysis with 10 studies, but the one with many more patients will give much more statistical weight to that one study, even if the smaller studies were actually methodologically better). As a result I have seen almost simultaneous meta-analyses on the same subject in different journals coming to different conclusions.
- There was a really good article looking at the pyramid of the value of different types of clinical evidence (see http://ebm.bmj.com/content/21/4/125.short?rss=1&ssource=mfr , or Evid Based Med2016;21:125-127 doi:10.1136/ebmed-2016-110401 ) which, unlike other “evidence pyramids” in the literature over the past 20 years, dismissed meta-analyses/systematic reviews, and highlighted, for example, that study design itself (i.e. an RCT) does not necessarily mean that it is a “better” study and should be the one influencing clinical practice just because of its design, over a good cohort study (they demonstrate this by their schematic pyramid of evidence-based medicine having wavy lines separating the types of studies, instead of straight-line clear-cut separations of the value of studies by their design. and they do not include meta-analyses/systematic reviews in the pyramid). To me, RCTs are clearly limited by their exclusion and inclusion criteria, and suffer from reductionism (see prior blogs, but basically reducing “n” patients into some mathematical average of, e.g., a 53 year-old patient, 35% female, 78% white, 37% diabetic, with no renal failure and 56% on aspirin……”), and trying to apply the results to a totally different individual patient you are treating with different ethnicity, comorbidities, meds, etc.
- Guidelines (also not included in the pyramid of the value of evidence-based medicine, above):
- There has been an unfortunate evolution of clinical guidelines, with a few dramatic shifts over the decades:
- The older guidelines were written by the NIH or similar governmental organization, with an emphasis on bringing in different experts both within the field and, at least to my experience, some outside of the field (e.g. clinical people), and providing a more consistent, less biased, and independent validation mechanism for the recommendations
- Perhaps related to ideological or financial imperatives, newer guidelines are more often being channeled back from the governmental agencies to professional societies, creating a few problems:
- Guidelines may not reach the same conclusions: e.g. the early versions of the Am Diabetic and Am Heart Assn guidelines on blood pressure goal. Then, what is a clinician to do??
- The professional societies’ guideline-writing groups often do not include practicing clinicians (at least from what I’ve seen), but mostly the higher-ups (i.e., mostly researchers) in the professional societies. There is often a significant financial conflict-of-interest with many guideline-committee members, though this is being watched and reported more now than before, more with some professional societies than others. But, beyond those direct financial/other interests of some of the specialty society leaders, I would guess that it is not easy/comfortable for others within the societies to be critical of them (they are the “leaders”, with disproportionate influence within the writing committee and within the specialty society)
- And there are a huge profusion of guidelines, from all of these societies, to the point that it is pretty impossible to keep up with them
- However, I think the real reason that guidelines are not considered part of the “evidence pyramid” noted above is that there is no external validation metric used for these guidelines: there are a group of specialists sitting around a table and making recommendations about how we should treat patients, and with an inherent conflict-of-interest above and beyond those of specific leaders promoting a technique or drug which they may personally benefit from. Is it surprising that the American Urological Association has historically been much more aggressive in pushing for PSA screening? Or the American Cancer Society historically pushing for more cancer screening? Or the American College of Radiology promoting more mammograms?
- So, the best model to me is reverting to the way guidelines used to be created, as currently done in other countries having a single uniform approach to guidelines (e.g. the NICE guidelines in the UK are pretty exemplary to me: very thoroughly researched, with, I think, pretty unbiased and thoughtful recommendations), using the best external validation metric to promote the best, least-biased recommendations based on known data and relatively unbiased expert opinion and informed by practicing clinicians. probably the best we have now in the US is USPSTF, though they also have an important-to-know filter of usually needing strong support from RCTs to really endorse an approach (e.g., see http://blogs.bmj.com/bmjebmspotlight/2016/08/30/1114/ which does not recommend lipid screening in adolescents, despite what I think is pretty compelling though circumstantial evidence, basically because there are no good 30-40 year studies following 12 year-olds, randomized to diet/exercise/perhaps meds at some point, and looking at clinical outcomes).
- There has been an unfortunate evolution of clinical guidelines, with a few dramatic shifts over the decades:
- Using on-line sources for quick guidance (e.g. Up-To-Date, etc.)
- These are also not on the “evidence pyramid”, for reasons similar to the guidelines issue: the entries are the non-validated opinions of a few individuals about how to evaluate, diagnose and treat patients. There are no upfront disclosures of commercial interest (if you click on an author’s name, then on disclosures in Up-To-Date, you can get the info, but it is a few clicks away, and, I would guess that a busy clinician looking for a quick answer probably does not do this a lot. And then the information is that the author gets money from perhaps a specific drug company. And, I would also guess, most of us primary care clinicians have no idea which meds that drug company makes and therefore which suggested med in the Up-To-Date review might be promoted more…).
- That being said, I do not know a clinician (including myself) who does not use one or more of these sources pretty often, to get quick guidance about what to do with the patient in front of them…. it is so easy, typically has a review of the relevant studies, and gives very clear guidance. The only issue is bias and reliability…..
- Misquoting references
- As mentioned in a few blogs, sometimes the articles misquote references, claiming incorrectly that a previous study came to a certain conclusion. So, it is useful to check the original article when an article makes a statement about another article that seems out-of-line. This is a lot of extra work, though way easier than it used to be (often you can click on a hyperlink of the reference, or do a quick online search. Easier than going to the library…)
- Even more commonly (still not very common), articles sometime make reference to a citation which is incorrectly cited (i.e., you look at the article cited and it has nothing to do with the author’s point??An error by the author/journal editor in making sure that the citation matches??)
- Supplemental materials
- Oftentimes, some of the most important material is relegated to the supplemental material (including important subgroup analyses, methodologic issues, data backing up some of the article’s conclusions, conflicts-of-interest, etc.) which really give lots of insight into the real value of an intervention. These are only accessible online (an issue if you do not subscribe to that journal) and are, I think, a significant impediment for many clinicians to access. In cases where I cannot get a specific article and have emailed the author for a copy, I only get the PDF, and unless I want to pay $30-50 to get the article through the journal (which I am not), I cannot see the supplementary materials.
- Using not-so-relevant clinical endpoints
- There has been a trend to using composite endpoints (perhaps to make the likelihood of an intervention’s benefit higher and more likely to be statistically significant) which just don’t make sense, such as combining a really important outcome with much less important ones. For example, a recent blog looked at CPAP for OSA (see http://blogs.bmj.com/bmjebmspotlight/2016/10/03/primary-care-corner-with-geoffrey-modest-md-cpap-does-not-reduce-cardiovasc-risk/ ), assessing CPAP utility for the composite endpoint of hard cardiovascular events plus the development of hypertension. If there were benefit for significant hard cardiovascular events, I would be quite inclined to suggest CPAP for my patients. But if CPAP only decreased hypertension a little (but statistically significant), I would treat that by reinforcing lifestyle changes, or using a med if needed, and would not prescribe CPAP. Or, another example: the ADVANCE study, which looked at tight blood sugar control on the effects on hard CVD outcomes plus diabetic nephropathy. This seems pretty silly. We know from many studies that tight control helps prevent diabetic nephropathy. The more important clinical issue is cardiovascular benefit or harm. And adding a known quantity of decreasing nephropathy into the “composite” endpoint just dilutes/distorts the results. This study really highlights the general issue of lumping together non-equivalent outcomes (it is hard to argue that developing early nephropathy is somehow equivalent to, and should be numerically added to, CV deaths or nonfatal strokes; or in many other studies, lumping together all-cause mortality with need for an additional clinical procedure). I raise these issues as examples, but this is really a very common finding. And this approach of combining endpoints may be worse now, since a large percent of the studies done are designed by drug companies, etc., which have a vested interest in the most positive outcome. And sometimes one cannot disaggregate the individual outcomes without access to the supplementary material….
- As I have railed about in many blogs, I am really concerned that the FDA accepts surrogate endpoints for some clinical diseases. The most evident one is using A1C as the end-all for new diabetes meds. Personally, I don’t really care so much about the A1c, just what really happens to patients. Many of the new drugs approved do decrease the A1c (though only a little, in most cases), yet have significant and serious adverse reactions (see many blogs in http://blogs.bmj.com/bmjebmspotlight/category/diabetes/ ) which undercut their utility significantly (e.g., as cited in many prior blogs: rosiglitazone does well in lowering A1C, just unfortunately increases cardiac events…)
So, I am writing this blog mostly because I have been doing these blogs for several years now, have been reading lots of articles, have the (perhaps) benefit of seeing the evolution over decades of clinical research and the medical-political-social-economic structure of both the research being done and how it is reported, and am pretty frequently struck by some of the not-often-acknowledged gaps and concerns of that literature and its effect on clinical practice. I would recommend reading the “evidence pyramid” article in the BMJ Evidence-Based Medicine journal referenced above, since it does comment a bit on some of these (and did stimulate me to write this). But, of course, I should also comment that all of the above are my observations (i.e., not validated by an independent group), but at least I have no (i.e., zero) conflicts of interest, other than the bias to a real skepticism in reading articles and guidelines, or of being an early adopter of new meds/procedures…..