Most Effects Are Smaller Than We Think

Photo: OliBac

I saw a patient the other week who complained of intolerable hot flashes for the last several months.  They were happening day and night, often awakening her from sleep, and after a series of questions, I realized they were significantly interfering with the quality of her life.  So I suggested she begin hormone-replacement therapy.

“What about the increased risk of breast cancer?” she asked, alarmed.

“Anyone in your family who’s had it?” I asked.

She shook her head.

“Then your baseline risk is average,” I told her.  “It’s true that studies have shown an increased risk in breast cancer in women who take hormone replacement, but that increase in risk is smaller than people commonly think.”

“I’m nervous…” she said.

I told her I understood her concern.  Then I explained how I think about risk and benefit when trying to make a decision to start a therapy.

ABSOLUTE RISK VS. RELATIVE RISK

Absolute risk represents one’s baseline risk of something bad happening, usually expressed in terms of their risk over a year or a lifetime.  For example, the average risk of developing breast cancer in the U.S. over a woman’s lifetime is 12.7% (several things can make that risk higher, of course:  a positive family history of breast cancer in a first-degree relative, for example, or the presence of a BRCA mutation).  But for the general population, most women won’t get breast cancer.  In fact, 87.3% of them won’t.

Relative risk, in contrast, represents the percentage increase or decrease over and above one’s baseline risk that one experiences as a result of belonging to one population compared to another (being a teenager compared to being an octogenarian) or as a result of one intervention compared to another (taking hormone replacement or not).  A recent study, for example, reported that women using combination hormone replacement (an estrogen and progestin) for 15 years or more had an 83% increased risk of developing breast cancer (though incidentally the same study showed estrogen-only replacement conferred only a 19% increased risk).

This seems at first glance to flip-flop the risk.  Rather than a woman having a lifetime risk of 87.3% of not getting breast cancer, it now appears if she uses combination hormone replacement therapy for more than 15 years, she’ll have an 83% chance of getting breast cancer.

But if this is what you concluded, you’d be wrong.  Why?  We have to remember the 83% risk is a relative risk, meaning we can only interpret its significance in terms of its effect on our absolute risk.

Because the average absolute lifetime risk of an American woman developing breast cancer is 12.7%, if she took combination hormone replacement for more than 15 years, her new absolute risk wouldn’t be 83%.  It would be 12.7% x 83% = a 10.5% increase in absolute risk, which then added to the baseline absolute risk of 12.7% would be 23.2%.

Now, a lifetime risk of getting breast cancer of 23.2% isn’t insignificant.  But it’s far less than the 83% relative risk implies.

The best way to decide whether or not to take the hormone replacement, I told my patient, was by weighing how miserable the hot flashes were making her against her fear of a 23.2% lifetime absolute risk of getting breast cancer.  And that, I told her, was a personal judgment.  In response, she told me I’d actually made the decision harder for her because the hormone therapy wasn’t tempting with a lifetime absolute risk of breast cancer at 83% but was at a 23.2%, given the severity of her symptoms.

THE GOOD AS WELL AS THE BAD

Unfortunately, though the increase in absolute risk for most interventions turns out to be less than most studies imply, so do the decreases in absolute risk they offer as well.  Take the example of aspirin.

Studies show in patients who’ve had a heart attack that taking one aspirin a day reduces their relative risk of having a heart attack over nearly a 10-year period by almost 50%. In patients over the age of 80, for example, whose absolute risk of having a heart attack can be as high as 12% in just the first six months following their first heart attack, this amounts to a recalculated absolute risk of 6%.  Arguably still significant, but not nearly as much as the 50% relative risk reduction commonly bandied about in medical circles.

On the other hand, in men without known coronary disease (though importantly the same hasn’t been demonstrated in women), studies suggest taking an aspirin a day confers a relative risk reduction of 32%.  Not quite 50%, but not too bad.  But, again, because this 32% is a relative risk reduction, we can only sort out the change in absolute risk reduction it represents by first knowing the baseline absolute risk of the population of men without known coronary disease.  That population, it turns out (depending, again, on their risk factors), may have as low as a 2% 10-year risk of having a heart attack.  Which means a 32% relative risk reduction translates into a new absolute risk reduction of 2% x 32% = 0.6%, then added to the baseline absolute risk equals a recalculated absolute risk of 1.4%.  When we consider also that aspirin use increases the absolute risk for peptic ulcers by about .5% per year (5% over ten years), the benefit of using aspirin to prevent heart attacks in low-risk individuals (dropping the absolute risk from 2% to 1.4%) seems outweighed by the risk of peptic ulcers (at least 5% over the same time period—or more depending on your baseline level of absolute risk) such aspirin use poses.

An interesting question arises:  why do most studies in the medical literature tend to report both risk and benefit statistics in terms of relative risk?  I don’t think it’s as a result of a conscious attempt to make risks and benefits seem greater than they are (in most cases, at least).  I do suspect there’s an unconscious bias at work, however.

We all want to have interventions available to us that work and work well.  If you scan the medical literature with a full knowledge of the difference between relative and absolute risk, however, it becomes clear that the true magnitude of impact most interventions have is actually quite modest.

This isn’t to say medicines don’t work, that we shouldn’t use them, or that their effects aren’t often wondrous.  But in attempting to modify risk, we may all be guilty—researchers, doctors, and patients alike—of believing we’re altering our destinies to a greater degree than we actually are.  I find myself sometimes surprised to hear how significant some researchers feel about what I consider small changes in absolute risk reduction and have to remind myself that what each of us considers a significant reduction in risk isn’t set in stone by a committee but rather by each individual according to his or her life circumstances and proclivities.

My patient, for example, was being made so miserable by her hot flashes that, after a prolonged discussion, she decided to try hormone replacement therapy for six months.  I suggested if it worked that we could then taper the dose gradually and perhaps stave off her symptom’s return, exposing her only to a small increase in her absolute lifetime risk of breast cancer (in many women, covering them with medication in the immediate post-menopausal period with hormone replacement therapy often leaves them free of hot flashes thereafter).  I told her the decision was hers as she was the one experiencing life with frequent hot flashes.  I just wanted to make sure she understood the risks correctly.  Almost nothing good in medicine—or life, for that matter—comes without counterbalancing risks that tend to give us pause.  Which is why it takes courage to embark on almost any course of treatment, courage to mitigate our understanding that even when we think everything through and make our choices as carefully as we can, things still sometimes go wrong.

Next WeekWhen A Beloved Pet Dies

14 comments to Most Effects Are Smaller Than We Think

  • Very useful article to help us (“the masses”) make a little more sense out of the sometimes dizzying array of medical claims.

    And I might add to that, what appears to be a strong “Western” bias on treatments.

    Perhaps I could use that segue to ask you a question; especially since you are practicing “Eastern” philosophy in your own life:

    Do you have opinions (medical or otherwise) on the efficacy of so-called alternative treatments, holistic medicine, energy healing, and the like?

    I ask not just in the abstract (although I would be very interested in reading your thoughts about these fields), but rather with some personal interest, as my wife was just diagnosed (via a targeted blood test) with rheumatoid arthritis. Her symptoms are relatively mild at present (soreness in her fingers and hands), but her RA factor was very high.

    I guess my question to you is—given Western medicine’s unknown cause of RA—would you recommend investigating alternative therapies, and do you have a suggestion for me as to how best to begin such an investigation (since the medical community appears not to put much stock in them).

    Thanks for any thoughts, and as always, for your insightful articles.

    Steven: I’m willing to believe anything, no matter how nuts it seems at first glance—if it can be proven. There are, in fact, plenty of alternative medicines and alternative medical interventions that have been studied for certain conditions and found to work. Why, for example, acupuncture can reduce the nausea brought on by some chemotherapy, I have no idea—but empirically it clearly does. Yet it’s critically important to recognize that the alternative medicine explanation for why something like acupuncture works in general has never been proven. Until it is, such an explanation is so much hot air. Alternative medicine may be freer in advancing theories about what causes certain diseases like RA, but until they’re proven, they’re just that—theories. You can, of course, act on a theory without proof—and personally I don’t mind, as long as your action has been proven not to cause harm.

    To answer your question specifically about RA, no, I wouldn’t pursue alternative therapies, or at least not at the expense of pursuing therapies that have been proven to work. There are a lot of theories out there about what causes autoimmune diseases like RA (too much antibiotic use altering our gut flora, for example) and one or more of them may even be right. But the fervor with which some alternative medicine practitioners believe these theories is wholly unjustified. Beware the snake oil salesman.

    Alex

  • kittylit

    That was WAY too confusing. Too many numbers and percentages. Put it into real words so that we can understand the concept please.

  • Anna-in-N.

    Hmmm, “kittylit,” your answer to Alex is a good example of the fact that different people read the same article and come to different conclusions. For years I was wondering how to interpret medical statistics. My math is not very good, but when I read, for example, that there is a risk of 20% and it decreases by 100%…it still is 10%, but a pharmaceutical company could “rightly” tout that their medication decreases the risk by 100%, which sounds on first reading as if the risk is gone.

    I suggest that we “forget” about all the numbers and be alert that many statistics (and not just in medicine) are often stated in a way that leads to drawing wrong conclusions, sometimes intentionally, sometimes out of a unconscious bias.

    Alex, thanks for a thoughtful Monday-morning-read.

    Anna

  • Dale

    Thank you for a particularly enlightening post. I have always thought that the incidence of breast cancer was MUCH higher than 12.7% and I’ve always found that hard to comprehend in view of the fact that no woman in my own family (quite large and going both forward and back several generations in either direction) has ever had breast cancer. I was on “estrogen only” therapy for about 12 years after a hysterectomy and stopped when all the publicity about increased risk hit the newspapers. This post puts the therapy in perspective and relieves my mind. Thanks again.

  • Janet

    Alex,
    You always enlighten by your clarity and open-mindedness on so many complex issues. Your last article reminds me of the quote about statistics and lies. Researchers and marketers would probably have us not perform the second step of the equation, which is to ask: “What percent of what number?” I wish it was a requirement to give the full, straight-forward statistical implication of a study. In health care, we often make decisions based on a little information, which may be misleading, and a lot of fear and ignorance.

    I think of you as a “Catcher in the Rye,” trying to keep people from falling off the cliff of misinformation and narrow thinking.Thank you for this mini course in statistics and for all the wisdom you share.

    Janet: Thank you for such high praise. I’ll keep trying to live up to it.

    Alex

  • Lil Gluckstern

    I really appreciate your article and the understanding it promotes. I also like the common-sense approach you espouse. However, after nine years of HRT, I developed stage 2 breast cancer and had to have a mastectomy. There is no history of any kind of cancer in my family except maybe a great-grandmother. I would also explore alternative methods if they were studied. I thought I was relatively safe. It didn’t turn out that way.

    Lil: Unfortunately, your case proves that 23.2% is not an insignificant number and that 23 out of every 100 women starting with average risk for breast cancer who use HRT for close to 15 years will get it. Which is why all decisions about risk and benefit need to be individualized to each person. I hope it all worked out okay for you in the end.

    Alex

  • Kevin

    Another really insightful presentation of what is a confusing realm, generally. Thanks for the good presentation of facts and how to interpret them.

  • Chuck Wolber

    Hi Alex,

    I believe you may have misused the word “theory” when you were replying to Steven. You said, “…but until they’re proven, they’re just that—theories. You can, of course, act on a theory without proof…”

    A theory explains why something happens and is supported by observation and evidence. Your use of the word theory in the above quote seems to imply that something can be a theory with no evidence backing it up.

    I believe the word you were probably looking for is “hypothesis.” A hypothesis generally describes an idea that does not (yet) have any evidence to back it up.

    Please accept my apologies if this comes off in a negative manner. Too often, I hear the ignorant refrain “well it is just a theory” used to derisively dismiss well supported scientific ideas.

    Chuck: Mmmm. I think you’re splitting hairs. I consider “theory” and “hypothesis” synonyms, both defined as a proposed explanation for observable phenomena. A theory/hypothesis may or may not be supported by evidence. I would agree it’s important to recognize that as explanations for observable phenomena, many theories/hypotheses have so much evidence to back them up they should be accepted as fact (e.g., the “theory” of evolution). On the other hand, a theory strongly backed by evidence can be proven incorrect or only partially correct by new evidence, as when Newtonian mechanics was superseded by Einstein’s theory of relativity. Having said all that, you do have a point that I used the word theory in a way that suggested it meant a proposed explanation without evidence to support it, which is probably as incorrect as defining it as a proposed explanationwith evidence to support it.

    Alex

  • This stuff is pretty obvious, but still it needs to be explained. Good job.

  • Giselle Massi

    Alex,

    Several years ago I was directed to try Sweet Annie’s Herbs http://www.sweetannie.com for menopausal hormone balance. It came highly recommended from a trusted source. This herbal formula and some nutritional changes ended the hot flashes and sleep disruption. Now postmenopausal and thriving, just want to pass along what might be a solution for others in your circle of healing.

    Best wishes for your novel.
    Giselle

  • Michael

    The human mind does not seem to “take” well to the concept of risk. We really have to build up to an understanding and take time to settle into the reality of what can be controlled, what cannot be controlled, and how much can and cannot be known.

  • [...] Alex Lickerman used a discussion he had regarding hormone replacement therapy and breast cancer as an opportunity to explain absolute versus relative risk. It’s a an issue we’ve tackled in Covering Health before (Thanks, Ivan), but the [...]

  • [...] Most Effects Are Smaller Than We Think by Alex Lickerman    [web | twitter | facebook] Learn the difference between absolute and relative risk, a critical skill for making risk-based decisions, especially medical decisions. [...]

  • [...] Take simvastatin (brand name Zocor). That is, if you have coronary artery disease. (This is one of those drugs that doctors joke should be put in our water supply.) A landmark trial called the 4S Study (click on the “Look Inside” button to read the article) showed that people with heart disease who take simvastatin will reduce their risk of dying from any cause by 30% (relative risk). [...]

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