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MicheleS

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Dear Edge-- Pls see the article below.  Your thoughts??  My 1st thought was that the grp receiving hypnotics were sleep-deprived (hence the Rx for a hypnotic!) and were therefore ALREADY at a greater risk... ie, there's a confound there...  My 2nd thought is that xanax is not a hypnotic.  However, they list a bunch of benzos... Ideas??  I know I should stop relying on xanax for a variety of reasons.  However, 0.5 mg at night helps me sleep.  I have reduced my dose significantly but haven't weaned off already.    Don't want to worry that the drug I am taking to quell worries is going to kill me! I was under the impression that ativan and xanax (though not without *other* risks) were pretty risk-free in the cancer recurrence department... thanks in advance for the help. xxoo

Hypnotics Linked With Increased Mortality, Cancer

Elsevier Global Medical News. 2012 Feb 27, S Worcester

Hypnotic drugs are associated with a more than threefold increase in the risk of death, even when prescribed in limited quantities, according to findings from a large matched cohort study.

The risk was increased more than fivefold among those receiving the highest quantities, Dr. Daniel F. Kripke of the Scripps Clinic Viterbi Family Sleep Center in La Jolla, Calif., and his colleagues reported in BMJ Open.

In addition, the use of hypnotic drugs was associated with an increased incidence of cancer among those receiving higher quantities.

The hazard ratios for death in 10,529 patients from a large health system who received hypnotic prescriptions for poor sleep, compared with 23,676 matched controls with no hypnotic prescription, were 3.60 for those prescribed 0.4-18 doses per year, 4.43 for those prescribed 18-132 doses per year, and 5.32 for those prescribed more than 132 doses per year, the investigators reported (BMJ Open 2012 [doi:10.1136/bmjopen-2012-000850]).

The "modestly increased statistically significant" elevations of incident cancer were seen in those in the middle and highest tertiles of prescribed doses (hazard ratios, 1.20 and 1.35, respectively), and the hazard ratio for lymphomas and for lung, colon, and prostate cancers were even greater than those for current smoking, they added.

The associations held in separate analyses of several different hypnotics, including new short-acting hypnotics and older hypnotics, and after poor health was controlled for. Analyses were performed for zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates, and sedative antihistamines. The highest mortality risk was with eszopiclone.

The data also were adjusted for age, sex, smoking, body mass index, ethnicity, marital status, alcohol use, and prior cancer.

Even after different classes of comorbidities and each patient's overall burden of comorbidities were considered, the results remained robust in each comorbidity group.

"Whereas the raw death rate of the user cohort was 4.86 times that of non-user controls, adjustment for all covariates ... with stratification by comorbidities only reduced the overall HR to 4.56," the investigators wrote.

Subjects in this study were members of a large U.S. health system, and had a mean age of 54 years. All were followed for an average of 2.5 years between 2002 and 2007. Patient data were derived from longitudinal electronic medical records, and hypnotic users and nonusers were well matched with respect to age, sex, period of observation, and BMI. They did not differ in ethnicity, marital status, or smoking status, the investigators said.

The findings, which support those of numerous prior studies that also suggested a link between hypnotics and increased mortality and between hypnotics and cancer, are important given that hypnotic drugs are among the most widely used treatments in medicine; an estimated 6%-10% of adults in the United States used hypnotics in 2010, the investigators reported.

Of note, the top third of hypnotic users in this study were prescribed nearly 93% of all the prescription doses of hypnotics.

"Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using less than 18 hypnotic pills per year," they wrote. The minimal impact of the major confounders that were controlled for in this study suggest it is unlikely that confounding of other inadequately assessed confounders could explain the high mortality rate seen with hypnotics.

As for why the association exists, multiple causal pathways have been demonstrated, the researchers noted.

These include, but are not limited to, mixed-drug overdoses and increased incidences of depression, impaired motor and cognitive skills, sleep apnea, gastroesophageal conditions, and infections. All of these, the authors pointed out, could contribute to mortality, such as by automobile accidents with impaired motor and cognitive skills or by cancer with gastroesophageal conditions and infections.

The findings are limited by the fact that the electronic health records used in this study provide information on medication orders only, and not on dispensing or ingestion of the medications. The investigators also were unable to control for depression, anxiety, and other emotional factors. Still, they asserted that the findings raise concerns about the use of hypnotics.

Rough order-of-magnitude estimates suggest that in 2010, hypnotics may have been associated with 320,000-507,000 excess deaths in the United States alone, the investigators reported.

Although this study cannot define what portion of the mortality associated with hypnotics was directly attributable to the drugs, the consistency of the estimates suggests that the effect of hypnotics was substantial.

"Even 10,000 yearly excess deaths caused by hypnotics would be too many," they said, concluding that it is prudent to weigh the evidence of mortality risks, as shown in this and 24 prior studies, against the meager benefits of hypnotics, in order to reconsider whether even short-term use is sufficiently safe.

Dr. Kripke reported a family interest in an investment corporation, which has a small percentage of its assets in stock of Sanofi-Aventis and Johnson & Johnson. The other authors reported having no relevant financial disclosures.

nosurrender

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Reply with quote  #2 
I do not think there is a link at all based on this. Especially the way this study is presented.
You are more in tune with data like this than I am, but think about it. People who have cancer probably are prescribed more sleep meds or tranquilizers. That skews the data. Also, it does not show a clear cut connection basing it on "electronic medical records"
If you need xanax to help you sleep for heaven's sake, don't let a study like this keep you awake! ;-)
Love ya,
g


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MicheleS

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Reply with quote  #3 
ohhhh Edddddgee!!!  you out there? hint-hint!

xxoo

edge

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Reply with quote  #4 
Michele:

I'll take this up tomorrow, but in short - much ado about nothing.


Constantine Kaniklidis

Breast Cancer Watch

edge@evidencewatch.com



edge

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Reply with quote  #5 

Hypnotized

The cohort study conducted by Daniel Kripke and colleagues at Scripps concluded that receiving a prescription of any hypnotic benzodiazepines or the non-benzodiazepine zolpidem (Ambien) was associated with increased mortality, and that for those prescribed high doses, cancer incidence also increased.

 

But the study design brings several serious, and several fatal, limitations.  I'll provide a "dirty dozen" although I uncovered at least that much more, and it goes to demonstrate again my oft-repeated message of  (1) the abysmal level of (un)quality of the vast preponderance of published studies, and (2) the lost art of critical appraisal:

 

  1. Cohort studies are restricted to at best a demonstration of association, not causality, the latter required a randomized trial.  Therefore we cannot conclude safely on the evidence that hypnotics are in fact themselves responsible for any increased mortality observed.
  2. Despite the fact that the researchers made adjustments to help control for various potential confounders and variations (such as age, gender,  ethnicity, marital status, body mass index,, smoking and/or alcohol use, prior malignancies), it is notoriously difficult to adjust for such complex factors completely, so their potential confounding influence may have been only partially controlled, and still other unknown factors may influence the association (see below).
  3. Another limitation is the possibility that hypnotics users and non-users differ in other medical factors and comorbidities that may account for their disparate mortality and cancer incidence, such as the presence of chronic diseases.
  4. One critical methodological failure that undermines the claimed causality is the fact that the study was unable to control for emotional / mental factors such as anxiety, depression, and other disorders (confidentiality restrictions on such diagnoses bar release of  such data).  Yet clearly such emotional/mental conditions may themselves be essential confounding factors.
  5. Still another failing was that the study was conducted via prescriptions, but without any monitoring of number of prescriptions filled, or whether the medication was in fact taken, or whether the medication was taken properly and as prescribed. But over-users and abusers, and under-users, and non-users, can again clearly distort the findings, as such non-standard behaviors may themselves be associated with excess mortality risk.
  6. There is some inconsistent claims re the methodology followed: the authors state [under "Methods"] that "Patients diagnosed with major cancer (apart from non-melanoma skin cancers) before the period of observation or within the first 0.05 years of follow-up were also excluded", yet the authors throughout also claim that prior malignancies were controlled for (via the  Cox proportional hazard model, although we could find no evidence of this): these two claims cannot be jointly maintained since if priors cancers were controlled for, then they were definitionally not excluded, and of course in the converse one cannot control for a factor that is not present by virtue of exclusion.  A close examination of the article and of all tables and supplementary material fails to resolve this contradiction.
  7. Another fault is that alcohol use was classified as a dichotomous variable, based on patient's self response to the elicitation of alcohol use in solely  yes or no query, but in a methodologically sound trial, alcohol consumption should be an ordinal, not binary, variable in the Cox proportional hazards model the author's used, and clearly alcohol related CNS depression cannot legitimately be presumed equivalent between low and high alcohol consumption. This alone is fatal, as alcohol is a known dose-dependent CNS depressant and an agonist in GABA receptors, raising the very real prospect of potential synergistic action with benzodiazepines to induce sedation, especially as  the supplementary data provided by the authors shows a significant prevalence (35 - 45%) of alcohol use in hypnotic users, so there might have been critical differences between the hypnotic users and the control group to confound the results and introduce selection bias.
  8. The authors also analyzed the hazard ratio (HR) for incident cancers in hypnotic users compared with non users, finding it to be statistically significant for some cancers(lymphoma, colon and lung cancer), but the mean follow up of this cohort study was 2.5 years, and it is accepted knowledge that lung, prostate and colon cancer are several years in development. This makes it plausible that hypnotic users had an undetected cancer before any  hypnotic prescription, and that cancer development was therefore independent of hypnotic use.
  9. There is also the strong possibility of selective overdiagnosis bias: hypnotic users would differ from non users with respect to insomnia and sleep related problems, and so may have been more carefully examined during hospital visits especially for prostate and lung cancer).
  10. The authors fail to note that there is an absence of experimental evidence for any carcinogenic potential of hypnotics, the exception being a single prior study conducted by none other than the main author himself, so any plausibility of connection must await studies done by other researchers.
  11. Worse still, the cause of death was not reported, and despite speculations by the authors of how hypnotic use might  indirectly lead to increased mortality (such as compromised cognition and balance), nonetheless insomnia itself is associated with an increased risk of mortality. Oddly the authors claim that there are several large studies that have found that insomnia is not a significant mortality favor, but my own review of the data fail to find any such thing, but rather that most of the articles that support that contention were written again by the main author (Kripe) himself, making for what's called a confirmation bias, since the relationship between insomnia and mortality was dismissed against the robust data that insomnia is indeed associated with an increase in mortality. So the claimed increase in mortality observed in the study may not have  been due to hypnotics but to insomnia, independent of hypnotic use.
  12. Further, other comorbilities ought to have been included as coviarates: osteoporosis and prior fracture history might be relevant in geriatric patients, given a well-established  increased mortality risk in geriatric patients post-fractures, and with more than 60% of the cohort being women, it was incumbent on the authors to have considered and controlled for osteoporosis which may have had different prevalence between the hypnotic users and non users.

 

Conclusion: the available evidence of this study of of accumulated data to date of an association between hypnotics and mortality is insufficiently robust and exhibits severe and often fatal methodological compromises, and the limitations of this particular study render it underpowered to sustain its own conclusions. 



Constantine Kaniklidis

Breast Cancer Watch

edge@evidencewatch.com

 

 

MicheleS

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Reply with quote  #6 
{{{Edge}}} you are my hero. 

Now, I task you with figuring out the flaws in the alcohol studies. ha!

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