• How big was the risk? Not only were the "cardiovascular and cerebrovascular events" not defined, the number of such events was not released. Assessing risk in the absence of such information is difficult. (See "Research Basics: Quantifying Medical Risk," at right.) The announcement did not even report the relative frequency of the events -- that is, did the events occur twice or three times or four times as often in the naproxen group?
But thanks to the persistence of journalists, a few relevant numbers have emerged. Reporters have quoted study investigators as saying that there were 70 events altogether; and the occurrence of events among naproxen patients was 50 percent higher than among those taking placebo.
Based on these numbers and the number of patients in each study group -- a figure available on an ADAPT study Web site (www.jhucct.com/adapt/pdf % 20documents/factsht.pdf) -- it is possible to calculate the likely magnitude of the naproxen risk. Assuming that Celebrex posed no increased risk to patients (the NIH announcement stated that "no significant increase in risk for Celebrex was found in this trial"), we calculate that over about three years, cardiovascular and cerebrovascular events occurred in 3.7 percent of patients taking naproxen, compared with 2.5 percent of patients taking placebo. (See "What Was the Likely Risk of Naproxen in This Study?" below.) If the figures in the news reports are correct (that is: 70 events; 50 percent higher risk with naproxen; Celebrex and placebo have the same risk), no other mathematical solution is possible.
You don't have to take our word for it: You can do the math yourself, following the steps we outline at www.vaoutcomes.org/washpost.php. Be warned: If the word "algebra" triggers long-forgotten high school nightmares, you may want to enlist your son or daughter for the task. Although the math involves using algebraic equations to solve for three unknowns, it is actually straightforward.
Similarly, we can compute what the worst-case scenario would look like. Assuming (absurdly) that there were no cardiovascular and cerebrovascular events in the Celebrex group (that is, Celebrex reduced the risk to zero in the study), the events occurred in 5 percent of naproxen patients compared with 3.3 percent of those assigned to placebo. To test this or other scenarios, try the interactive calculator at www.vaoutcomes.org/washpost.php.
These calculations suggest that naproxen could pose a risk, but that risk would affect less than two people per hundred over about three years. And the risk must be considered in light of who the study participants were -- patients age 70 and older. Because the chance that a person will experience a stroke or heart attack is strongly related to age, any added risk for younger people posed by naproxen -- if it exists -- would likely be considerably lower.
The Bottom Line
Although the precise risk of naproxen in the ADAPT study is hard to know -- because we don't know what constitutes a "cardiovascular or cerebrovascular event" -- it is possible to deduce from the information available that the size of the risk is, at most, modest.
In addition, the news from ADAPT conflicts with other credible studies that have found either no increased cardiovascular risk with naproxen or even some evidence that it actually protects the heart.
But more concerning is the nature of the NIH announcement. It failed to distinguish between naproxen users in the study -- who were taking the medication only in hopes of preventing Alzheimer's disease -- and naproxen users in the general public who take the medication because of its demonstrated effectiveness in treating musculoskeletal pain. For the study volunteers, the combination of an unknown benefit and even a small possible risk may well have been enough to justify halting the trial. We say "possible risk" because the number and type of events have yet to be verified and released by the study investigators.
But for people choosing to take naproxen for pain relief, the balance between risk and benefit is very different. Here, the benefit is known -- and directly experienced by the user -- while the risk is less certain (because many of these people are younger or are taking naproxen only intermittently).
One thing is clear. No one should have to guess what is going on.
The NIH and FDA announcements should have communicated the basic information needed to understand the nature and magnitude of the risk (if any) posed by naproxen. If it was too soon to release the answers to the two basic questions -- risk of what? and how big is the risk? -- it was too soon to frighten the public.•
Steven Woloshin, Lisa Schwartz and H. Gilbert Welch are physician researchers in the VA Outcomes Group in White River Junction, Vt., and faculty members at Dartmouth Medical School. They conduct regular seminars on how to interpret medical studies. The views expressed do not necessarily represent the views of the Department of Veterans Affairs or the United States Government.
