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Making decisions … and making them work
This year is characterized by making a leadership decision of sufficient importance to attract a huge amount of our attention and cash flow, albeit only about 0.015 percent of our $15-trillion gross national product. How do we make decisions? Do we analyze Democrats and Republicans with respect to their overall "comparative effectiveness," or is it their "comparative ineffectiveness" that influences our thinking? It's generally settled that many joined one tribe or the other and stick with it out of family tradition and to avoid being labeled disloyal or a flip-flopper. A relative few voters make the difference in the outcome, and both tribes pander to their emotional hot buttons, rather than the integrated whole.
Does past performance predict the future? I'm reminded of that phrase investment funds use: "Past performance is not indicative of future results." This suggests both hope and fear. Why not use the same honest phrase for climate change or mammography, the PSA test or the product insert for a drug? It pretty much provides cover for decisions on how to vote, buy wine or to cheer for the Chicago Cubs.
Four decades ago, Prof. Ron Howard of Stanford University, an expert on decision analysis, introduced the term micromort, a unit of risk, and a one-in-a-million chance of death. The concept has been broadly applied across many human activities, including those that put us in motion with exposure to Newton's laws by bungee jumping, flying, driving, skiing and the like. There are less immediate risks, such as exposure to sunlight, nitrosamines, cosmic rays, osteoporosis drugs or anesthesia. A confounder of such a formality is the human tendency to be influenced by short-term observations, such as a recent cruise ship mishap off Italy.
The egregious behavior of Enron and Tyco executives, Bernard Madoff or the "London Whale" at J.P. Morgan also come to mind as rare events. Hopeful investors gambled in collusion with professionals, and they lost. Cruise lines report ca. 0.1 micromorts encountered per ticket purchased. For commercial air travel globally, the numbers in recent years have averaged <0.003 micromorts per million passenger kilometers traveled, <3 nanomorts/km. Considering the United States alone, we've fortunately had no such fatalities in five of the years since 2001.
But what is the risk of dying of any cause in any given year? Today, in the United States, that number is 8 millimorts/year across the ages, from 1 mm/y in the college years to 50 mm/y from 1975 to 1984. About 5 mm/y on average can be attributed to a combination of malignancies and cardiovascular disease.
I've long contended that the risk of disease is given less attention than the risk of treatment, even though disease prevention is an available option often not taken. I stick with my theme that medical interventions should be relatively safe and relatively effective and relatively economic compared to allowing disease to progress untreated.
Micromorts are thought-provoking and can also be stress-inducing at my age. With respect to drugs, there are a variety of confusing terms that are not consistently applied, but are important to differentiate. These include medication errors, adverse drug events, adverse drug reactions (ADRs), side effects and hazard ratios.
Errors are mistakes related to human failings in writing or reading prescriptions, dispensing, patient adherence to the dosing regimen or misdetermining circulating concentration. An event is harm done by a drug itself, whatever the cause. A reaction is an unintended drug response caused by normal use, such as an allergy, headache or QT interval prolongation in the ECG. This term is frequently used synonymously with side effect. A hazard ratio describes a relationship between one drug and another with respect to a specific unintended outcome.
ADRs are typically listed in direct-to- consumer advertising with no attached probabilities, for which we propose the impractical microADRs or milliADRs. A recent New England Journal of Medicine paper (May 17, pages 1,881-1,890) is titled "Azithromycin and the Risk of Cardiovascular Death." The authors examined responses to a typical five-day course of therapy and compared with the use of two alternate antibiotics or none. During the five-day period examined, there were 29.8 micromorts for no antibiotic, 31.5 for amoxicillin and 85.2 for azithromycin. The latter showed a hazard ratio of 2.88 for azithromycin versus no antibiotic.
The paper is well done, but context is very important. A colleague saw a summary and asked, "Is azithromycin really three times more dangerous than other antibiotics?" All subjects were Medicaid patients; 77.5 percent were women with a mean age of 48.6, and many were prescribed medications for hypertension. The authors wisely described the risk as slight and small. Yet my colleague was thinking triple the risk!
Too often, we read of the relative risk of drug A versus drug B without benefit of the absolute risk of either in relationship to the absolute risk of the condition treated. The same ambiguities apply to mammograms and PSA tests. We see the statistics, yet we still can't decide. A sensible decision for a population may have a bad outcome for an individual. This is what scares people about the concept of comparative effectiveness.
Returning to politics, I hear that one tribe is perpetrating a "war on women" and the other "favors abortion." One tribe wants to "eliminate all regulations on business," while the other "wants gas to be $10 a gallon." None of these are factual. When will we learn that campaigning and governing correlate very poorly? While it's true that past performance may not be indicative of future results, if you flip a coin 99 times and it comes up heads each time, I'm voting that something is funny, and the next flip will also come up heads.
An evidence-based decision suggests the crowd in either tribe in Washington, D.C. is prone to adverse reactions and high hazard ratios compared to some cohorts we've seen in the past. Let's take them off the market and try again until we get something that works.
Peter T. Kissinger is professor of chemistry at Purdue University, chairman emeritus of BASi and a director of Chembio Diagnostics, Phlebotics and Prosolia.