Evidence isn't Everything
Evidence-based medicine and statin decision-making
A doctor told Mike, an active middle-aged man, that he should take a statin drug because of high cholesterol.
This makes sense. High cholesterol levels play a role in heart disease and statins reduce cholesterol levels. Most compelling to me are genetic studies—which find that people born with gene variants for low cholesterol have strikingly lower rates of heart disease.
But, as I showed in my first newsletter, plausibility is not enough. You need evidence.
In fact, the evidence for statins is amongst the strongest in all of medicine. More than 100,000 patients have been enrolled in numerous trials of statins vs placebo, and the results are consistent: statins produce a 20-25% reduction in future cardiac events.
The trials are blinded, so patients don’t know if they are taking the drug or the placebo. Serious adverse events are rare; the more common side effects, such as muscle complaints, occur in equal rates in the placebo and statin arms.
A super-clever study from researchers in London lent support to statin tolerability. They enrolled patients who had stopped taking statins because of complaints into an N-of-1 trial, in which each patient got a suitcase of 12 pill bottles corresponding to each month. One pill bottle had the statin tablets, one bottle had a matching placebo, and the other was empty.
Patients had an app to record symptoms each day. The results were profound: patients felt best during the months of taking no tablets, but they had essentially the same symptoms during the months they took placebo as they did taking statins. IOW: statins can produce symptoms, but it is not due to the statin chemical, rather the act of taking the statin tablet. About half of the (previously intolerant) patients started taking their statin after they were shown the results.
Enter our unbiased Martian. She would look at this evidence and say it’s a no-brainer. Mike should take the medication.
But evidence isn’t the only factor in medical decisions.
Three decades ago, a Canadian doctor named David Sackett coined the term evidence-based medicine or EBM.
True EBM combines the best evidence with clinical expertise and patient values.
Le’t start with patient values. My friend, Dr. Andrew Foy, from Penn State University, likes to think about minimizer and maximizer personality styles of patients.
A minimizer would look at a 25% reduction in future events, and think it’s not worth taking a pill every day; a maximizer would want to do everything to reduce the events and take the pill.
But many people fall in the middle between full-on minimizer and maximizer.
Now enter clinical expertise. We can help Mike make this decision by showing him exactly what a 25% reduction looks like. It depends on the baseline risk. (You can easily get your baseline risk by using an online calculator.)
The table below shows how baseline risk affects how much actual (or absolute) risk reduction one gets from a statin.
In a person with a 20% baseline risk, statins reduce the chance of having a future event by 5%. That is four-fold more reduction you would get if your baseline risk is 5%. The higher the risk at baseline, the more the probability gain.
The picture above shows something called NNT, or the number needed to treat to prevent one cardiac event. (Mathematically, the NNT is 1/ARR.)
For the 20% baseline risk, NNT holds that you have to treat 20 patients with statins to prevent one cardiac event. Perhaps you see the problem: that frame has it that 19 patients get no benefit.
But that’s not exactly right.
The same London research group have proposed a better way to think about the use of preventive therapies. They used mathematical modeling of gains in lifespan to show that taking a statin (or any preventive therapy) is a bit like a lottery.
Before I tell you about the lottery effect, first think about what a trial result actually gives you. In the beginning, I said statins reduce the risk of future cardiac events by 25%. That is the average effect. Some patients in the trial get more and others get less benefit.
The London researchers’ model shows that big gains are concentrated in a small minority of patients.
For example, men aged 50 years (like Mike) with national average cardiovascular risk have mean lifespan gain of 7 months. However, 93% of these identical individuals gain no lifespan, while the remaining 7% gain a mean of 99 months.
This makes sense, right?
If the statin prevents a fatal heart attack at age 51, you’d gain many years. But balanced against that huge benefit is the chance that you’d get no benefit.
Another friend, Dr Luis Correia, likes to say trials merely give us bags of probabilities.
The job of the clinician with years of expertise and a sound sense of evidence is to help patients choose the strategy that is most aligned with their values.
I wish that was it. But it is not. Clinical expertise can also help embrace uncertainty.
One of the best papers on this in regards to statins comes from Professor Rodney Hayward from the University of Michigan. (It’s open access.)
He first explains that much of the public discussion over statins centers on how the drugs would promote public health. A small reduction in cardiac events spread over millions of people would add up to a lot fewer heart attacks.
But individual decisions must be made on an individual basis—as guided by those three circles I showed you above.
Hayward then provocatively points out the unknown unknowns.
What people appreciate less is the frequent unknowables in medicine. The null never can be proved, especially when it is something difficult to study, such as whether being on a statin for 20 to 25 years has no major long-term adverse effects. Could being on a statin for 25 years result in a 25% increase in decline in cognitive function or a 35% acceleration in the decline in muscle health associated with aging?
For example, if being on a daily statin for 25 years had even a modest negative impact on common aspects of aging, then it would not just reverse the marginal benefits of routinely starting a stain at 40 years of age, it also would be a public health disaster.
How likely is it that such undetectable long-term harm exists? Who knows because how can you estimate the frequency of something that is currently undetectable?
Medicine-guided-by-evidence has oodles of unknowables because most clinical trials only follow patients for 2-5 years. Yet many preventive therapies are given for decades.
I hesitated adding Professor Hayward’s quote because there are vigorous online voices who oppose statin drugs. That is fine, they don’t have to take them.
The counter to longterm worries about cognition would be that a leading cause of cognitive decline is vascular disease in the brain. Since statins reduce vascular events, the drugs may actually reduce the incidence of cognitive decline.
Hayward’s point on uncertainty, stands, though. We just don’t know.
If you have read this and still don’t know what Mike should do, I have succeeded.
This is how the vast majority of modern medicine works. The clarity of fixing a broken bone, using antibiotics for bacterial pneumonia and opening a blocked coronary in an acute heart attack are the exceptions not the rule.
One of the goals of Stop and Think is to embrace uncertainty.
Mike now knows that statins will reduce his chance of a future cardiac event; he knows that in blinded studies, the drugs have minimal side effects. He understands that his degree of risk reduction is expressed in probabilities, and he can now decide if it is worth it for him to take the pill. He can also factor in the unknowables.
This is how EBM is supposed to work. (I used statins in this example, but the same principles apply to other medications, procedures, screening tests and surgeries).
Another friend, Dr. Saurabh Jha, has penned one of the best columns on statins. God and Statins is a masterpiece.