Friday, November 12, 2010

Counterintuition and the importance of clinical trials

Justifying or adopting things which "just make sense" can get you into a lot of trouble in medicine. This kind of mental shorthand is frequently used by people who are interested in promoting products or ideas without doing the science to confirm that they are effective. Many of the nutritional supplements available for purchase have some degree of science behind them, but just because something works in a lab, doesn't mean it will work when you put it in a human.

This is where the role of the randomized clinical trial becomes critical. I want to give you a few examples of ideas which "make sense" but have been modified or soundly rejected after the appropriate science was done.
  • Let's start with an easy one, "inotropic agents". Let's say your heart doesn't squeeze well and you have heart failure. There are drugs (inotropes) that can make it squeeze harder. Sound like a good idea? Turns out that using inotropes shortens the average life span for heart failure patients. This might be for a number of reasons, but it turns out that these drugs increase the risk of fatal arrhythmias and they increase the workload of the heart possibly worsening the disease process.
  • On the opposite side of the coin, we have beta blockers. These are drugs hat slow down the heart and "make it weaker". There was a time when beta-blockers were contraindicated for patients with heart failure, after all, who would take a patient with a weak heart and give them a drug that slows down and weakens the heart!? It turns out, though, that in addition to slowing the heart rate, these drugs decrease the demand for oxygen and have other beneficial effects on heart health to the point where beta-blockers are a standard of care for anyone with systolic heart failure (where the heart doesn't squeeze well)
  • Coumadin (warfarin), aspirin, Plavix (clopidogrel), heparin, fondaparinux, and several other classes of drugs are all blood thinners. So, if all these drugs thin your blood, why do doctors prescribe warfarin so much? Simple, that's what the evidence says to do. All the drugs thin your blood and increase your risk of having some kind of bleeding, but if warfarin reduces your risk of stroke, and Plavix doesn't, why would you take Plavix?
  • After people have heart attacks, the scar makes the heart more prone to arrhythmias. This is a big problem for some people because the arrhythmias can be deadly. Now, let's say you hang around in the hospital for a couple of days recovering from your heart attack and your doctor notices premature heartbeats. We have drugs that can make those early heartbeats go away. Maybe if we do that, we can prevent arrhythmias and prevent people from dying. Well, it's a good thing someone thought to to a trial of that, because it turns out that giving drugs to suppress those early beats actually increases your risk of dying! This has to do with the fact that some anti-arrhythmia drugs can actually slightly increase your risk of arrhythmia. (Source: the CAST trial)
  • If you have high blood pressure, how low should you try to make it go? Is less than 130 okay? What about 120? 110? At some point dropping blood pressure becomes a bad thing. Thankfully more and more clinical trials are helping to home in on the solution to this problem, however the same conundrum exists regarding diabetes. How low should your blood sugar be? It turns out that recent trials have shown that while controlling blood sugar is crucial at preventing progression of the disease, trying to get your blood sugar down to where a normal person's is could cause more complications (hypoglycemia) and not be beneficial.
  • When you have surgery, one many potential complications is to get an infection at the site of your surgery. Thankfully, we have antibiotics that prevent that, right? It depends. A big trial in the New England Journal of Medicine (Bennett-Guerrero et al. Sept 9, 2010) showed that using an antibiotic coated sponge actually INCREASED the number of infections!
  • Last one I'll mention for now is a drug called torceptrapib. This potential blockbuster was the first agent that was thought to directly increase your "good" (HDL) cholesterol. People were very excited because statins, which lower your "bad" (LDL) cholesterol have made billions and billions of dollars for the pharmaceutical industry. Unfortunately, when they tried it out in people, the HDL molecule it "made" didn't seem to work quite as well as the ones you make on your own AND, the drug raised blood pressure. It never made it to market, because despite sounding like a good idea, it didn't pan out when someone actually tested it in real people and measured a meaningful clinical outcome.
Anyway, these are just a handful of examples of how your intuition can lead you astray and just because something is PLAUSIBLE does not make it fact.

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