The National Health Service in the United Kingdom spends over 300 million pounds per year on antidepressants (475 million USD).

Yet in a large study comparing antidepressant drugs with placebos, Irving Kirsch found no significant difference between placebos and ‘active’ drugs except for patients with severe depression.

Last Sunday night the research was discussed in a CBS 60 Minutes report. During her interview, reporter Lesley Stahl challenged Kirsch: "You're saying if (patients taking antidepressants) took a sugar pill, they'd have the same effect?"

Kirsch replied: "They'd have almost as large an effect, and whatever difference it would be, would be clinically insignificant."

Stahl was incredulous. "But people are getting better taking antidepressants, I know them. We all know them."

"People get better when they take the drug, but it's not the chemical ingredients of the drugs that are making them better. It's largely the placebo effect," Kirsch replied.

Kirsch’s research raises many provocative questions. If placebos appear to cure depression, is depression a real disease? How can a sugar pill cure depression? If sugar pills work as well as drugs and have fewer side effects, why not use them?

Nobody doubts that depression can be very serious. (And any patient taking or considering antidepressant medication should consult a qualified practitioner before making treatment decisions.) Instead, it means placebos are particularly good at curing depression. This can be achieved through several mechanisms. The sugar in the pill can influence insulin levels and induce a cascade of physiological effects. Moreover the doctor’s friendly manner, also part of the placebo, has been shown to make mildly depressed patients feel better.

The reason placebos aren’t prescribed is doctors deem them to be unethical. This is because (among other reasons) doctors should only prescribe treatments that are proven to be effective. But effectiveness is often established by demonstrating superiority to placebos; so to prove they are effective, then need to be more effective than themselves, which is impossible. Moreover, as Stahl noted, the ‘real’ drugs have known and serious side effects. So not prescribing placebos might be even less ethical.

Whatever the answers to these difficult questions, surely we can come up with an answer to the placebo ethics dilemma that costs less than 300 million pounds per year. More research, please!

The original proponents of EBM have always argued for “evidence at the bedside” so that we can make the best decisions for patients nearest to the point “where the rubber hits the road”. How often do we clinicians actually look up the evidence in real time during or soon after a consultation to change the management or the advice we give to a patient?

I saw a lady in her 40s in our cardiology clinic this week. She has been followed up every 1-2 years in clinic for bicuspid aortic valve (BAV). Basically, the aortic valve is at the outflow of the left ventricle (the major pump of the heart) and usually has three cusps which open and close to ensure flow of blood in the right direction through and out of the heart. In bicuspid valves, people are born with only two cusps and over their lifetime, they are more prone to developing narrowing of the valve (“aortic stenosis”), with a significant probability of needing aortic valve replacement during their lifetime. The idea of screening and surveillance is that any narrowing or malfunction of the aortic valve can be picked up early, and the person can be referred for surgery more quickly and effectively than if their disease had progressed.

BAV is the most common abnormality of the heart valves, occurring in 1- 2% of the general population and is twice as common in males as in females. Reassuringly, a recent cohort study of patients with BAV found that they have similar survival rates to the normal population. However, “given that serious complications will develop in over a third of patients with BAV, the bicuspid valve may be responsible for more deaths and morbidity than the combined effects of all the other congenital heart defects”. The potential problems are narrowing or leaking of the aortic valve, infective endocarditis and enlargement or “dilatation” of the aorta. In other words, BAV is common, has serious complications and there is a treatment which improves survival (aortic valve replacement). Therefore, BAV is a condition which meets Wilson’s criteria for screening.

I was asked by the lady if her children were at risk of BAV and whether they should be screened. I did not know the exact answer so I looked online with the patient. There is a 30% risk of aortic dilatation or BAV in first degree relatives (parents, children or siblings) of people with BAV. A more recent study showed that 20% of first degree relatives of people with BAV may have undetected BAV themselves. It turns out there are no NICE guidelines or formal UK/European guidelines for whether we should be screening relatives or how we should be doing it.

Interestingly, across the pond, the Americans have guidelines for familial screening and the literature seems to suggest it. Therefore adult children of patients with BAV should have an echocardiogram to check that they do not have a BAV which would mean that they should also be followed up. Valvular heart disease is a bigger health issue than we imagine.

There are four take home messages for me. First, EBM can be done at the bedside-it is meant to be the most practical of clinical sciences. Second, there is no harm as a clinician in saying “I don’t know” and looking it up. Third, sometimes it is the obvious clinical questions which are still unanswered or debatable. Finally, practice can be changed.

An earlier TrustTheEvidence.net blog post on the geometry of evidence described the importance of network meta-analyses. These indirect methods of analysis compare the results from two or more studies that have one treatment in common when comparative effectiveness (CE) research is lacking.

What is comparative effectiveness research? To quote the US Federal Coordinating Council for Comparative Effectiveness Research Report to President Obama in 2009, it is defined as the:

“generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor health conditions in ‘real world’ settings”

Additional studies that compare one drug to placebo are not incredibly useful when we already know they work. The real challenge of evidence-based practice is determining which treatment to use when all ten available drugs are better than placebo. How do clinicians decide which one to prescribe? All too often decisions are built on studies lacking active comparators. This is not high quality care for patients.

A recent study published in PLoS ONE evaluated trials registered in ClinicalTrials.gov that focused on the top 25 topics identified as priority areas by the US Institute of Medicine (e.g. treatment of atrial fibrillation). The authors looked at studies conducted in the US between 2007 and 2010 and determined the prevalence of CE research.

Despite the importance of this research methodology, only 22% of studies were CE studies and their characteristics varied substantially based on the funding source. Primarily industry-funded studies had the shortest duration of follow-up and were more likely to report positive findings compared to studies with any government funding.

As usual, children get left out. Industry-funded studies were less likely to enroll children when compared to government or nonprofit funded trials. The lack of controlled trials in children is already a problem and there may be a perceptions among drug manufacturers that testing drugs in children brings the risk of increased liability.

The authors hypothesise that the increase in CE research will lead to an increase in the number of studies that fail to support new interventions. Not good for big pharma, but why?

First, trials with inactive comparators (i.e. placebo) are more likely to achieve favourable findings. On the contrary, CE studies tend to produce conservative results regarding the superiority of a therapy compared to other active treatments.

Second, industry-funded the majority of drug and device CE studies meaning that most were designed and conducted by the company marketing the product. There is substantial evidence that these studies are more likely to report positive findings supporting the use of a product. The PLoS ONE study provides further evidence that even in CE research industry-funded studies were more likely to report an outcome favouring the use of the intervention.

But it’s not all doom and gloom. The US has allocated $1.1 billion to CE research. This added investment of noncommercial funding will be critical to provide unbiased answers and evaluate under-studied populations (e.g. children). It’s about time we provide with stronger evidence.