{"id":1339,"date":"2017-07-17T15:03:32","date_gmt":"2017-07-17T15:03:32","guid":{"rendered":"http:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/?p=1339"},"modified":"2017-08-21T10:04:55","modified_gmt":"2017-08-21T10:04:55","slug":"primary-care-corner-with-geoffrey-modest-md-benzos-may-not-increase-mortality-risk","status":"publish","type":"post","link":"https:\/\/stg-blogs.bmj.com\/bmjebmspotlight\/2017\/07\/17\/primary-care-corner-with-geoffrey-modest-md-benzos-may-not-increase-mortality-risk\/","title":{"rendered":"Primary Care Corner with Geoffrey Modest MD: Benzos may not increase mortality risk"},"content":{"rendered":"

by Dr Geoffrey Modest<\/strong><\/p>\n

\u200b\u00a0The BMJ just had an article assessing mortality from\u00a0benzodiazepines\u00a0from a large US commercial healthcare database, showing minimal increased mortality\u00a0risk (see\u00a0doi.org\/10.1136\/bmj.j2941).<\/p>\n

Details:<\/strong><\/p>\n

— 1,252,988 randomly selected patients, comparing those initiated on a benzodiazepine during\u00a0a medical visit within the prior 14 days\u00a0vs\u00a01,252,988\u00a0non-initiators, from 2004-2013<\/p>\n

— all patients were required to fill at least one\u00a0prescription\u00a0for any medication both\u00a0in the 90 days\u00a0and 91- 180 days before the index date (ie, they were plugged into medical care and filling prescriptions), and high dimensional propensity scoring was done (see below).<\/p>\n

—\u00a0Mean age 46, 85% men, mean Charlson comorbidities score 0.5 (ie,\u00a0low), 5% smokers, 4% obesity\/overweight, 28% hypertension, 1% heart failure, 5% ischemic heart disease, 25% hyperlipidemia, 10% diabetes, 3% COPD, 5% asthma, 10% neuropathic pain, 20% back pain, 3% kidney disease, 10% cancer, 10% anxiety, 10% sleep disorder, 11% depression, 2% drug or alcohol misuse [reaffirming that this is a pretty healthy and younger\u00a0population overall]<\/p>\n

— Medications included SSRIs in 18%, opioids in 30%, barbiturates in 2%, antipsychotics in 2%, other anxiolytics in 1%<\/p>\n

— of note, in comparing benzodiazepine initiators vs non-initiators, prior to propensity scoring, the benzodiazepine group had more smokers, hypertensives, atherosclerotic disease, hyperlipidemia, COPD\/asthma, neuropathic pain, cancer, a lot more anxiety and depression, and were much more likely to be on beta blockers, steroids, opioids (35% vs 24%!!), anticonvulsants, SSRIs (22 vs 12%), and other hypnotics.\u00a0All of these characteristics were well-balanced after propensity score matching<\/p>\n

—\u00a0Short acting benzodiazepines\u00a0were more frequently prescribed, 75% of the filled prescriptions, and alprazolam was the most commonly prescribed of them (47.2%), and diazepam was the most commonly prescribed long-acting agent (87.8%).\u00a0On review of their supplementary materials, they did include clonazepam as a short acting benzodiazepine, though it’s half-life is actually quite similar to that of diazepam \u00a0(both about\u00a020 hours, sometimes much more: >60 hours)\u200b. Not sure why they did that.<\/p>\n

— main outcome: all-cause mortality, as determined by linking to the Social Security Administration Death Master File. The overall mean follow-up was 159 days for the benzodiazepine initiators and 146 days for the non-initiators.<\/p>\n

— secondary analysis: comparing mortality in patients initiating benzodiazepines with other active treatments (i.e. SSRI antidepressants), also with high dimensional propensity score matching<\/p>\n

 <\/p>\n

Results:<\/strong><\/p>\n

— over 6 months of follow-up, there were\u00a012.2 events per 1000 person-years in the benzodiazepine initiators\u00a0vs 6.9 events per 1000 person-years\u00a0non-initiators,\u00a0a\u00a078% increased mortality risk. But, given the\u00a0different baseline characteristics of these groups, probably\u00a0 the most relevant finding was that after the\u00a0high dimensional propensity scoring,\u00a0there were 5061 deaths in benzodiazepine initiators vs 4,691 in non-initiators,\u00a09.3 vs 9.4 events per 1000 person-years; HR 1.00 (0.96 1.04 ). ie no difference<\/p>\n

— a 4% increased mortality risk was observed in those on benzodiazepines when the observation period was extended to 12 and 48 months of follow-up.<\/p>\n

— benzodiazepines were\u00a0associated with a 9% increased risk as compared to those starting SSRIs<\/p>\n

— in subgroup analysis, older patients\u00a0initiating benzodiazepines with a longer half-life had no increased risk of all-cause mortality, however younger patients and patients using the short-acting benzodiazepines did have a 9% increased risk.<\/p>\n

Commentary:<\/strong><\/p>\n

— Propensity match scoring was used to mathematically control for potential measured\u00a0confounders. The high dimensional propensity score algorithm also used above\u00a0is an automated technique which prioritizes\/controls for more than 300 covariates that may serve as proxies for unmeasured confounders in large electronic databases. but it is important to reinforce that even large observational studies as this one do not enable us to draw definitive conclusions about causality:\u00a0there still could be unmeasured variables which are primarily responsible for any associations. This population overall was pretty healthy, those on benzodiazepines less so, emphasizing that there might well have been other significant differences between these groups (though the lack of association is reassuring, since these sicker patients, controlling for their measured\u00a0sicknesses but were\u00a0probably at higher risk for other unidentified sicknesses and more likely to have a less healthy lifestyle, and they\u00a0did not have higher mortality than the much less sick non-benzo initiators).<\/p>\n

—\u00a0As we know, benzodiazepines are frequently used in the outpatient setting, in 2008 approximately 5.2% of US adults aged 18 to 80 used benzodiazepines, increasing from 4.1% in 1996 to 5.6% in 2013. Similar numbers were found in British Columbia, Canada. Use increases with age, with a higher usage in those older than 50, especially for anxiety and sleep disorders. The concerns about their use in the elderly is related to prior reports of a threefold or more increased risk of all-cause mortality, even for short duration usage. And\u00a0concerns remain\u00a0about increased falls and fractures in the elderly. it should also be emphasized that this population above is a younger one, a selection bias related to the fact that this was a commercial healthcare\u00a0database.<\/p>\n

—\u00a0It seems pretty remarkable that in the overall population, 35% of those who initiated benzodiazepines were on opioids vs 24% who did not start benzodiazepines.\u00a0Given the apparent higher mortality of benzodiazepines in those on opioids found in a few observational\u00a0studies (eg, see blog<\/a>), it would have been useful to know specifically how the opioid subgroup fared. One concern that I have regarding the potentially increased mortality of combination of\u00a0benzodiazepines and opioids is whether it is really\u00a0from the combination\u00a0or from the patient\u00a0mortality associated with the conditions that the benzodiazepines might be treating (e.g. the\u00a0significantly increased\u00a0mortality of panic or other anxiety disorders).<\/p>\n

So,<\/p>\n

—\u00a0\u00a0the increases in mortality found in the\u00a0subgroup analyses above were very small, though statistically significant because of the huge number of patients evaluated\u200b. so, clinically they found essentially no difference in those\u00a0initiating benzos<\/p>\n

— from a clinical practice perspective,\u00a0this study to me is largely reassuring\u200b:\u00a0I have certainly seen many older patients (again, not well represented above)\u00a0who are severely functionally affected by\u00a0anxiety, resistant to non-pharmacologic therapies as well as non-benzodiazepine drugs.\u00a0I have prescribed benzodiazepines in many if them with excellent results. Preferentially I have used longer acting benzodiazepines, such as clonazepam\u00a0(though\u00a0as noted, they consider this a short acting benzodiazepine in the above study, but i think that might be an erratum), even in patients in their 90s. Patients certainly understand the potential increased risks of falls and possible increased mortality, but are desperate for immediate symptomatic relief.<\/p>\n","protected":false},"excerpt":{"rendered":"

Benzos may not increase mortality risk […]<\/p>\n

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