Commentaries

Number Needed to Treat (NNT); Number Needed to Harm (NNH) In psychiatric trials the numbers are  interesting because we think of treating Pr o b l e m s in diagnosis a r i s e d a i l y . We like symptoms) and may possibly reduce disorders like depression as we treat an understand what we mean when we say, “I some of the long term complications. infection, try one medication, titrate the think you have X.” We often don’t When we treat Parkinson’s or Alzheimer’s dose, then if not successful, try another know for sure, as in diagnosing Alzheimer’s , we are treating symptoms, and drug. Yet a very good result for treating or Parkinson’s diseases (PD), and we un- not altering the pathological process of depression may have an NNT of 3-5, derstand that we have a certain degree of the disease itself. We can tell if these drugs which means that only 20-30% of treated confidence in being correct. “I’m sure you “work” because the symptoms improve. patients are improved by drug, a ratio that have disease X; I’m pretty sure; I think you Complicating our concept of treat- would not inspire confidence in most of might…” We are less clear, I think, in how ment-prophylaxis is the problem of us, although this is in addition to the we classify the efficacy of our treatments. identifying suitable “biomarkers,” which benefit of placebo. And this NNT, which When we treat infections we expect cure are clearly defined metrics of the disease’s is fairly typical for psychiatric treatments, in 100% of our patients, and failing this, severity. How well does a con- compares favorably with the outcomes for we blame the organism for being resistant, trol pain, as measured by an accepted common medical treatments. the patient for not taking their medication pain scale? How does it control motor Should we be telling patients that our properly or having an anatomic or im- function in PD as measured by some ac- drugs are effective 30% of the time or less? munologic disorder. But this is not true cepted scale? But in the case of cholesterol, Do we really expect this result, which, I for the chronic ailments that afflict 75% which is not a symptomatic disorder but a suspect most readers will find uncomfort- of the elderly. We don’t treat hypertension “biomarker” of increased risk of vascular ably poor, when we prescribe or take a new because it is causing symptoms. It is the disease, we found that simply lowering it, drug, or do we expect that most of our “silent killer.” It is treated to prevent prob- which a recent drug did quite significantly, patients will improve? I note, in passing, lems, namely heart attack, stroke, kidney led to no decrease in the risk of heart that the results of double-blind trials and failure and atherosclerotic disease, and the disease or stroke, much like getting rid “real life” are quite different, with the pla- secondary problems each of these may then of the smoke, but not the fire. cebo effect of the doctor giving a known cause. Yet our drugs are not 100% effective I recently attended a stimulating lec- “effective” treatment, versus the measured even when they are “successful,” since we ture on the drug treatment of refractory placebo effect of simply participating in a confuse treating a for the disease depression. Once he got over the problem drug trial. I assume that the former is the with the disease itself. We reduce the likeli- of defining “refractory,” the speaker in- more potent, but perhaps not. hood of impending stroke and heart attack troduced the concept of “number needed We can stand things on their heads when we lower blood pressure. We do not to treat” and “number needed to harm,” and calculate the “number needed to prevent all strokes or heart attacks. We can which was a foreign concept to several in harm,” which is a measure of side effects. be 100% confident that we reduced the the audience. It’s a valid and sometimes How many subjects are treated before blood pressure, but that doesn’t translate useful way to estimate treatment effect. causing an iatrogenic complication? This into improved health for the vast majority It is helpful for estimating efficacy for is a less useful number because the poten- of the treated patients since they are not prophylactic and treatment therapies, tial side-effects are considerably larger and going on to have strokes or heart attacks. especially when taking cost into account. often less well-defined than the precisely By treating them they are not “getting bet- For example treating systolic blood pres- defined treatment effect. Death, however, ter.” They are “not getting worse.” sures above 160 in the elderly, one needs to is a rather well-defined outcome and there A large percentage of our contem- treat 120 people to prevent one stroke in a is no universally acceptable ratio to estab- porary treatments are intended to reduce year. Carotid endarterectomies performed lish a certain benefit to counter-balance risk, not treat symptoms. An operation for by highly competent surgeons must be the risk of death in a minute percentage a pinched nerve solves a problem, whereas performed on 40 arteries to prevent one of the population. The extremely small a carotid endarterectomy is intended to stroke per year in patients with asymptom- increase in death rate for people taking prevent one. Treating diabetes controls atic stenosis. Clopidigrel is mildly better at atypical antipsychotics earned those drugs blood sugar and therefore the problems of reducing stroke risk than aspirin but 250 a “black box” warning by the FDA, which hypoglycemia (confusion, seizures, coma) people need to take the drug in place of made the drugs harder to use. and hyperglycemia (confusion, seizures, aspirin to prevent a single stroke per year, The NNT can be used to calculate polyuria, polydipsia, weight loss, stroke- at about 150 times the price. financial outcomes. If it costs a certain 2 Medicine & Health/Rhode Island amount for each stroke in terms of work NNT is useful to keep in mind when Disclosure of Financial Interests lost, money spent on hospitalization and we choose treatments, especially in the Lectures: Teva, Ingelheim Boehringer; rehabilitation, not counting the intan- elderly. Sometimes when a patient com- General Electric gibles, one can see that spending tens plains about having to take yet another Consulting: United Biosource; Buba- of thousands of dollars in extra medica- drug, or about side-effects, it may be that loo, Halsted, Reitman LLC; EMD Serono; tion cost may still save money even if a the marginal return on the drug use is Genzyme; Teva; Acadia; Addex Pharm; seemingly negligible number of people simply not worth the cost. Schwarz Pharma are spared the stroke or myocardial in- Research: MJFox; NIH: Cephalon; farct. Seatbelts save lives and enormous EMD Serono; Teva; Acadia amounts of money even though few – Jo s e p h H. Fr i e d m a n , MD Royalties: Demos Press people ever need them. Co r r e s p o n d e n c e e-mail: [email protected]

Contagion as a Fiscal Problem  An a l l e g e d l y n e w communicable d i s e a s e e n t e r s o u r i m m e - propriately notified and their active assistance requested, diate community. We hear about it—cloaked in frightening including their superb laboratory facilities and mobile metaphors—in the local newspaper and its existence is verified epidemiologists? in the other publications within the state. Learned commentators • Is the disease of sufficient economic and social impor- then remind us of the mayhem wrought by prior pestilences and tance—for this community—to justify a formal preven- pandemics; and both our wise statesmen and clergy admonish tive medicine campaign? us, perhaps urging a day of fasting and repentance, to prepare • Is there the political will to use public moneys to confront us for the worst. the epidemic? The United States, in the 1920’s and Important questions necessarily arise: Is this an utterly new 1930’s was confronted with a near epidemic of venereal pestilence or merely a recurrence, such as influenza, of an infec- disease, particularly syphilis and gonorrhea. Many re- tious disease that has repeatedly arisen amongst humans in the ligious communities were strenuously opposed to any past? Is the infection confined to humans, such as poliomyelitis, federal anti-syphilis program, contending that the core or does it transcend species barriers, such as with influenza, and disorder was sinful behavior and hence not in the domain concurrently infect swine, birds or other creatures? of public health and certainly not within the realm of We will assume now that this newly arisen pestilence affects federal responsibilities. By the mid-1930’s, a cautious both children and adults indiscriminately, is suppressed by no public education program was instituted with posters in known antibiotic and results in a relatively high . A public bathrooms declaring: “Stamp Out Venereal Dis- local committee is then assembled to determine what the commu- ease!” as well as an earnest program in the armed forces nity might do. Their decision might be: (1) to do nothing beyond to combat venereal disease. the customary use of private medical offices, clinics and emergency • Are there religious scruples that might cause sufficient rooms; or (2) to appeal to the citizenry to participate in specified numbers to resist the contemplated preventive medicine days of prayer, sacrifice, humiliation and fasting; or, (3) to encour- interventions (e.g., a recommendation for the use of age the civic leadership to proactively invest in known preventive condoms)? Or secular worries that vaccines might cause measures and community-wide educational interventions. autism? The decision is not a simple one: Community priorities • Are there medical interventions (such as enhanced water must be examined. The past experience of other communities purification methods or enforceable quarantines or vac- must be explored. And certainly a set of fundamental questions cines) which have been shown elsewhere to be medically will demand answers before tangible steps will be taken. proven and cost effective for this particular pestilence? • Do any of the preventive measures, such as a contem- • Is there certainty that the disease is communicable; that is, plated vaccine, carry significant morbidities and com- caused by a living organism such as a virus, a bacterium plications? (As an example, the original, crude Pasteur or a fungus? If communicable, how is it communicated? vaccine to combat rabies, devised in the late 19th Century, By air, by drinking water ? By physical contact (including was clearly effective medically but its use carried a high venereal intimacy)? Or by the intermediacy of an insect frequency of serious, and sometimes fatal, neurological such as a mosquito or tick? complications.) In the sphere of public health, there are • Have neighboring communities been similarly affected? no free lunches. And if not, have they been duly warned of the nature/ characteristics of this new ailment? A communicable disease—whether it be new or recurrent— • Has the United States Public Health agencies, particularly poses many challenges and choices for the affected community. the Centers for Disease Control & Prevention, been ap- Ultimately, of course, it resolves itself to a mixture of competing 3 Volume 95 No. 1 Ja n u a r y 2012