Do No Harm: Not Even to Some Degree

EditoRial http://dx.doi.org/10.5664/jcsm.2018 do no Harm: not Even to Some degree Daniel F. Kripke, M.D. 1 ; Robert D. Langer, M.D., M.P.H. 2 ; Lawrence E. Kline, D.O. 1 Scripps Clinic Viterbi Family Sleep Center, La Jolla, CA; 2 Jackson Hole Center for Preventive Medicine, Jackson, WY W e are grateful to Dr. Bianchi and colleagues for summa- rizing questions about our recent paper associating hyp- notics with excess mortality and cancer. 1 We are grateful to the Journal for this opportunity to provide organized answers to these questions. In the absence of adequate randomized trials extending for years, it is clinically important to assess the long-term risks and benefi ts of commonly prescribed hypnotics, using the best data now available and employing the most conservative ana- lytic strategies possible. We have done that. Dr. Bianchi and colleagues asserted that we confused correlation with causal- ity. We did not. We took pains to be clear that ours was an observational study and that some residual confounding was likely. Nonetheless, the robust associations of hypnotics with mortality and cancer that we found, increasing stepwise with increasing exposure, and virtually unchanged with multiple strategies for control, command attention and reassessment of common practice. It has been hard to report calmly that hypnotic use was as- sociated with 3.60- to 5.32-fold mortality risks. It would be wonderful if somebody could prove it is not so—and the risk could be overestimated—but scientifi c ethics require us to re- port what our data showed and to explain the possible implica- tions. Though the main responsibility for warning falls on the manufacturers who were informed of these risks years ago and on their FDA supervision, we physicians have a duty to warn also. We cannot hide risks, even if they might frighten patients out of taking hypnotics. Patients have a right to know. Some suppose that the increased mortality of hypnotic users was due to their insomnia, and that insomnia might explain the 3.60- to 5.32-fold mortality excess. It is true that because of the IRB’s interpretation of Pennsylvania law, we were unable to control explicitly for insomnia or depression. However, in our paper, 1 we referenced several studies which have found that in- somnia is NOT associated with signifi cant mortality. We know of no evidence that insomnia signifi cantly predicts mortality when hypnotic use, comorbidities, and other confounders are adequately controlled. A new example is found in the recently published representative national sample from Taiwan, where those with sleep disorders had signifi cantly less cancer inci- dence than those without sleep disorders among participants who had not received zolpidem, HR = 0.69 (0.62-0.78 95% CI). 2 Use of ≥ 300 mg/y zolpidem without benzodiazepines was associated with a cancer hazard ratio of 6.24 (4.13-9.43 95% CI), but even among the zolpidem users, those with sleep disorders had lower risk. Thus, sleep disorders could not con- ceivably explain the excess mortality or cancer associated with zolpidem prescriptions. Our paper also referenced studies showing that depression does not confound the association of hypnotic use with mor- tality. In Belleville’s Canadian sample, control for depression only reduced the hypnotics and tranquilizers mortality odds ra- tio from 1.40 (1.13-1.75, 95% CI) to 1.36 (1.09-1.70, 95% CI), which was not signifi cant. 3 Depression was not even a signifi - cant mortality risk factor when benzodiazepine use and other covariates were controlled. 4 In the Taiwan sample, the cancer hazard ratio for depression was 0.68 (0.53-0.88, 95% CI). 2 Thus, confounding with depression could not explain mortality and cancer associated with hypnotic prescriptions. What about sleep apnea as an explanation? Young and col- leagues reported that apnea-hypopnea indices < 30 were NOT signifi cantly associated with excess mortality in an adjusted model. 5 With AHI ≥ 30, the risk ratio was only 3.0 (1.4-6.3, 95% CI). The Sleep Heart Health Study had even more sur- prising results, wherein women (who use more hypnotics than men) had no signifi cant increase in mortality associated with any level of sleep apnea. Among men, signifi cant excess mor- tality was associated with AHI ≥ 30 only among those age ≤ 70 years. 6 Among both sexes of all ages combined, AHI ≥ 30 was associated with a hazard ratio of only 1.46 (1.14-1.86 95% CI). These apnea studies were not as extensively controlled for comorbidities as our study. Our hypnotic-associated risk ratios of 3.60 to 5.32 could not be caused by apnea risk ratios of only 1.46 or 3, even in the implausible event that all the patients pre- scribed hypnotics had AHI ≥ 30 but none of the controls. Could excess comorbidities among hypnotic users account for our 3.60- to 5.32-fold hazard ratios? Let us recall the data. In our stratifi ed analyses, we compared hypnotic users with con- trols having exactly the same classes of comorbidities, so co- morbidity diagnoses were matched. Even had we not employed matching and alternative forms of adjustment to control for co- morbidities, how could a 45% excess of comorbidities among the hypnotic users account for a 3.60- to 5.32-fold mortality hazard? It is true that we were unable to adjust for severity of comorbidities when they occurred, but since the diagnoses of comorbidities accounted for only a small amount of the mortal- ity hazard, where is the evidence that severity of comorbidities or uncommon comorbidities could account additionally for a much larger portion of the mortality hazard? No one has offered any explanation of how confounding could produce the signifi cantly different hazard ratios we ob- served between hypnotics and different cancers. Sanofi Aventis Journal of Clinical Sleep Medicine, Vol. 8, No. 4, 2012