This is a nice TED talk on the problem of publication bias. The FDA is complicit in this problem because they dont force drug companies to publish their studies. Consumers (doctors and patients) never get the whole story. No amount of critical appraisal skills can overcome this problem.
Ben Goldacre: What doctors don’t know about the drugs they prescribe
Truly sad… Not sure what any of us can do though short of going to the FDA website for every drug we prescribe (or at least the new ones) and seeing what was submitted for approval.
This week in the Annals of Internal Medicine another study (http://annals.org/article.aspx?articleid=1359238) has been published showing that biases in studies can lead to inaccurate results. Thus its really important to critically appraise primary studies. Unfortunately few doctors take the time to do so (I suspect, though I don’t have empiric proof to cite) and, despite EBM skills being taught for a decade now, few probably even remember how to do so.
Savovic and colleagues have done the most comprehensive attempt to quantify the effect of 3 design elements on the outcomes of randomized controlled trials: random-sequence generation, allocation concealment, and double blinding. First, what the heck do those terms even mean? In a randomized trial participants are assigned to study groups in a random fashion, akin to a coin flip. No one actually flips a coin but researchers usually use a computer program to generate a random number (random sequence generation) and this number determines the group to which a patient is assigned. For example, if the number is odd the patient goes into the control arm, if the number is even the intervention arm. The number generation needs to be unpredictable (ie random) and not just alternating odd and even numbers. Authors of studies should give enough information on how the random sequence generation was undertaken. As of 2006, only 34% of PubMed indexed trials did this adequately.
We don’t want those trying to enroll a patient into a study to be able to figure out to which arm the patient will be allocated or assigned. We want the allocation concealed. This is blinding of the randomization order or scheme. Concealed allocation helps guard against someone getting preferentially placed in one arm of a trial or another based on their prognosis. We don’t want sicker patients preferentially put in one arm and healthier ones in another. This would clearly bias the findings of the study. In a 2005 study, only 18% of randomized trials indexed in PubMed reported any allocation concealment.
Most doctors understand blinding. What they don’t understand is who should be blinded– everyone possible is the short answer. Blinding the trial participants and trial personnel avoids participants from being treated differently based on the arm of the study they are in. But what if you can’t blind the patients or the study personnel (for example in a study of a surgical procedure vs medical mgmt)? You blind the outcomes assessors. Statisticians should also be blinded. Interestingly, Benjamin Franklin is credited with being the first person to blind participants in a scientific study. Blinding is especially important if the outcomes are subjective (for example quality of life). Conversely, blinding is less important for objective outcomes like death.
Back to the study by Savovic and colleagues. The authors used some sophisticated techniques to acquire and analyze the data and I won’t bore you with the details. Just accept that they did a good job (dont all authors of studies want us to trust them and they usually disappoint us?). What did they find? Inadequately or unclear random sequence generation, allocation concealment and blinding led to exaggeration of intervention effects by an average of 11%. As expected, the effect was greatest for subjective outcomes. The greatest overestimate of treatment effect was seen with inadequate blinding (23% overestimation) followed by inadequate allocation concealment (18% overestimation).
These kind of findings always bother me for 2 reasons:
- We come to the conclusion that interventions are better than they are. We are falsely led to believe in much greater benefit than there likely is. We offer things to patients with the promise of more benefit than they will likely offer.
- Why do these flawed studies get published? Why dont reviewers and editors reject the publication of these studies or at least put a black box warning that the results are biased? I still can’t understand why we publish flawed research without labelling it as such. Why can’t researchers just design the study properly in the first place? It’s not like the elements of good study design are a secret.
What should doctors do to avoid using biased information?
- Read the pre-appraised literature like ACP Journal Club. The articles published in ACPJC are structured summaries of critically appraised articles. To be published in ACPJC a study has to be methodologically sound and clinically important. Articles with important methodological weaknesses will not be published.
- Find answers to questions in evidence-based textbooks, like Dynamed (https://dynamed.ebscohost.com/)
- If you have to read primary studies CRITICALLY APPRAISE THEM! It’s not hard. Each study design has its own set of questions against which you should judge the quality of the study (http://ktclearinghouse.ca/cebm/practise/ca). If you find the study is flawed either throw it away and find another one or realize biases almost always result in overestimation of treatment benefits and adjust your expectations accordingly.
This post is not about desirable personal characteristics but about 2 studies that have attempted to determine if PCI combined with optimal medical therapy (OMT) is better than OMT alone in patients with stable angina. This is an important question because a lot of costly PCIs are done on patients with stable angina. I am not a cardiologist so I will not comment on the technical aspects of these studies but will instead focus on design issues that I think temper the results of these important studies, especially FAME2.
FAME2 was released online this week by the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa1205361?query=featured_home) while COURAGE was published in 2007 (http://www.nejm.org/doi/full/10.1056/NEJMoa070829). COURAGE was the first trial to combine state of the art (at the time) PCI with state of the art medical therapy (which still holds true today) for CAD. COURAGE has been criticized because many of the patients were VA patients and for the use of mostly bare metal stents. Critics have ignored the fact that bare metal stents are similar to drug eluting stents (DES) in most outcomes except for restenosis.
FAME2 enrolled patients with stable angina, who had one coronary vessel with at least 50% stenosis that was suitable for PCI. Inherent in these inclusion criteria is the angiographic knowledge of the patient’s coronary anatomy. Often in clinical practice we make decisions on treatment without this knowledge; but based on symptoms and noninvasive assessments alone. Study design quality was generally good: randomization was used, randomization scheme was concealed, intention to treat analysis was used, the 2 study groups were similar at the start of the study, and the groups were treated equally other than the treatment under study. Patients and clinicians were not blinded but this is less important in this study as the outcomes were fairly objective.
So what problems do I have with FAME2? Whenever you read a study and identify a limitation you should always ask yourself what impact that limitation could have on the results of the study. I am especially trying to identify design issues that bias the results towards one group over the other.
- The endpoint of the trial is a composite of death from any cause, nonfatal MI or unplanned hospitalization leading to urgent revascularization. Patients would consider each component equally important in a good composite and clearly death would be much less preferred than urgent revascularization. Each of the components of the composite should have a similar biological mechanism and clearly they don’t. Finally the components of a good composite should be affected fairly equally by the intervention and here they aren’t (death is insignificantly reduced by 67%, MI is increased insignificantly by 5%, and revascularization is reduced by 87%). This doesn’t mean we reject the trial it just means you should look at each individual component instead of using the composite.
- All stenoses with a fractional flow reserve (FFR) <0.8 were treated with the current state of the art DES. Sounds great…..fix everything you see. The problem is that this biases the study positively toward the PCI group because if you fix everything and not just lesions that cause ischemia by functional testing you will leave fewer lesions to cause any problems in the future and thus need less revascularization.
- The trial was stopped early. Too early considering there were no formal stopping rules. Furthermore the trial was stopped because the PCI group needed less urgent revascularizations than the OMT group….a finding that was predictable as I mention in #1 above. By stopping a trial early you never know what the longer term effects of your study will be (both good and bad) .
- The landmark analysis using day 7 as the landmark point seems arbitrary and its rationale isn’t explained in the manuscript. This will also bias findings positively towards PCI because PCI has immediate effects whereas medications take more time to work.
- The study wasnt blinded and knowledge of the treatment arm could definitely influence treatment decisions. Knowing a patient was in the OMT arm and still having angina might lead to the recommendation of PCI more often than intensifying OMT.
So what should readers of FAME2 take away from the study? In patients with stable angina PCI only reduces angina and the need for future “urgent” revascularizations and this reduction is likely overestimated. PCI doesn’t prevent death and it doesn’t prevent MIs. COURAGE showed us the same thing. Optimal medical therapy works and we should strive to get patients on OMT as outlined by COURAGE and FAME2. Finally, all studies have limitations; there is no perfect study but understanding what effect the limitations would be expected to have on the outcomes can help us better temper the results.