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Archive for March, 2016

Primary Care Corner with Geoffrey Modest MD: Gout Management — AHRQ Report

31 Mar, 16 | by EBM

By Dr. Geoffrey Modest

A comparative effectiveness review from the Agency for Healthcare Research and Quality (AHRQ) was just published on the management of gout (see https://www.effectivehealthcare.ahrq.gov/ehc/products/564/2196/gout-management-executive-160314.pdf for the executive summary; or for full report, see https://www.effectivehealthcare.ahrq.gov/ehc/products/564/2195/gout-management-report-160314.pdf​ (138 pages, not including references, etc, but including the executive summary).

Key points:

  • 8 million patients in US have gout
  • Typical attacks, especially early in the disease, last 7-14 days without meds
  • Chronic gout tends to develop after years of increasing acute attacks, and may be associated with tophi (typically after 10 years of untreated gout)
  • Risk factors: hyperuricemia, but also some combo of genetics, hormonal, metabolic and dietary risk factors. also family history, advancing age, male sex, and early menopause in women. thiazides may also be a risk factor
  • The solubility factor of urate is 6.8 mg/dl, though there seem to be several factors that lead to urate deposition, including temperature, local pH, as well as the concentration of urate. Several studies (including the Framingham study) show that the 5-year incidence of acute gout in men increases from 10% in those with serum urate levels of 6.0-6.9, to 48% if serum levels are >8. And the risk is higher if there were a prior gout attack: the 1-year incidence is 30% if the urate level is 6.0-6.9; and >70% if urate > 8mg/dl.​
  • Key question 1 (acute gout treatment)
    • Colchicine works to reduce pain in acute gout (strength-of-evidence  SOE — high). this is typically 0.6mg tablets: 2 tablets right away, then 1 tablet every hour for 6 hours or until diarrhea)
    • Low-dose colchicine is as effective with fewer adverse effects (SOE — moderate). this is typically 2 tablets initially then only 1 more tablet one hour later
    • NSAIDs reduce pain  (SOE — high)
    • Doesn’t matter which NSAID one uses (SOE — moderate) [though digging into their supportive data, there really are no studies done looking at some of the more common NSAIDs, such as ibuprofen or naproxen, though my experience and my sense of prevailing experience is that these work just fine]
    • Systemic steroids reduce pain  (SOE — high)
    • Not enough evidence to comment on effect of meds on joint swelling, tenderness, ADLs, patient global assessment
    • Adverse effects with colchicine are mostly GI (23-77%), NSAIDs also GI (>10%, but <1% with serious GI issues like bleeds), steroid adverse effects are mostly from long-term use, except dysphoria, increased  blood sugar, immune suppression, fluid retention [i would add the not-so-common but severe avascular necrosis of hip/shoulder, which can occur with short-term use]
  • Key question 2 (dietary and lifestyle management of gout)
    • Insufficient evidence for anything for gout management (reducing dietary purines, protein, alcohol; increasing consumption of cherries, milk products, vitamin C; losing weight)
    • Insufficient evidence for anything for reducing serum urate levels (decreasing red meat, shellfish, yeast; or increasing low fat dairy, veges, cherries as compared to just weight loss and decreasing alcohol)
    • Insufficient evidence for Traditional Chinese medicine (herbs, acupuncture) on symptomatic outcomes
  • Key question 3: pharmacologic management of gout
    • Urate lowering therapy does NOT reduce the risk of acute gout attack in first 6 months (SOE — high)
    • But urate lowering therapy DOES reduce risk of acute attacks after 1 year of therapy (SOE — moderate)
    • No difference between febuxostat 40mg and allopurinol 300mg in lowering serum urate levels (SOE — high) [by the way, allopurinol has been around and used for >40 years]
    • Effect of feboxustat vs allopurinol on tophi — insufficient evidence
    • Using low dose colchicine or NSAIDs prophylactically does reduce gout attacks when beginning urate lowering therapy (SOE — high)
    • Longer courses of prophylaxis with colchicine or NSAIDs (>8 weeks) are more effective than shorter courses in preventing gout attacks when beginning urate lowering therapy (SOE — moderate)
    • Including dietary advice to urate lowering therapy — insufficient evidence
    • Adverse reactions for allopurinol: rash in 5%, mostly mild. can get bad reactions (TEN, Stevens Johnson, DRESS syndrome) but too rarely to be found in the studies (though risk of DRESS is higher if HLA-B*5801 allele is present). for febuxostat, abdominal pain, diarrhea, musculoskel pain (5-20%), but not statistically different from placebo; and no real difference in adverse effects from allopurinol (SOE — high)​
  • Key question 4: treatment monitoring of patients with gout
    • Utility of monitoring uric acid levels in those on meds – insufficient evidence
    • Treating to a specific target uric acid level reduces the risk of gout (SOE — low, but “logic supports some monitoring”
  • Key question 5: discontinuation of meds for patients with acute or chronic gout
    • Discontinuing meds after 5 years with urate levels <7 mg/dl, and where subsequent uric acid levels are <7 mg./dl off meds –insufficient evidence
    • Using low dose colchicine or NSAIDs for >8 weeks when beginning urate lowering therapy does result in fewer gouty attacks (SOE — moderate)

So, this report reveals the soft underbelly of medical studies. Gout has been around for eons. We have really old therapies that work (e.g. colchicine). There are thousands (?probably many more) studies on gout. But very few answered the above key questions directly (which are really the biggies for primary care). Of interest, despite the plethora of “insufficient evidence” above, they comment that even though there are not definitive placebo-controlled RCTs on the meds (this comment was only for meds!!!), they decided to give reasonable SOEs about the usefulness of the meds given the understanding of pathophysiology: i.e., there’s lots of inflammation, so steroids are good (and, they state it would probably be unethical to do a steroid vs placebo study). As are NSAIDs. Though there was no comment about (in my opinion, and as expressed before) the dramatic benefit of intra-articular steroid injections. Similarly for chronic gout: it is useful to lower serum urate levels. But there is scant evidence of “treating-to-target” or how long to give meds, and they give no recommendation. Though it is clear that serum uric acid levels is a strong predictor of acute gout and that some open-label extensions of studies have shown a graded relationship between achieved serum uric acid levels and risk of acute gout (the Am Col of Rheum suggests a goal of <6 mg/dl, which makes sense given the Framingham Study showing a 30% recurrence rate with uric acid levels of 6.0-6.9). Another issue is that even the “good” studies done often reflect a skewed population (e.g. in major trials of urate lowering therapy, the presence of tophi is >20%, whereas in primary care it is about 10%). But, I think that one of the big shortcomings to this review is that though they do rate meds for gout based on pathophysiology, they do not do so for nonpharmacologic approaches which also decrease urate levels (e.g., weight loss, low purine diet, decrease alcohol, decrease fructose), which to me reeks of a bias….

Bottom line:

  • The current analysis does include newer studies, but sheds little additional light because of the lack of rigorously assessed interventions. However, there are lots of guidelines out there, and I think they mostly make sense overall, despite the lack of rock-solid data (see http://blogs.bmj.com/ebm/2016/03/04/primary-care-corner-with-geoffrey-modest-md-oral-steroids-for-acute-gout/ for a recent article on steroids vs NSAIDs, but it includes my blog evaluating the Am College of Rheum guidelines from 2012). At least those older guidelines promote nonpharmicologic interventions and are pretty useful in clinical practice.
  • They dismiss using uricosuric agents because allopurinol works probably better and is easier to take, and requires less workup. No comment on losartan to lower uric acid levels, which is in the Am College of Rheum recommendations, and which I use preferentially in those with concommitant hypertension. (see doi: 10.1136/bmj.d8190​)
  • And a couple of points from my experience:
    • ​I see an 84 yo man with heart failure, CKD stage 2-3, with a documented symptomatically severe gouty attack, who went to an ER and was given oral prednisione, with some benefit. he came to see me and had prepatellar bursitis. I injected this with steroids, and he responded dramatically. Subsequent uric acid was 10.8. I decided to treat him with febuxostat (given his kidney disease and his really high uric acid, though I suspect allopurinol would have been fine) and his uric acid within weeks plummeted to 4.9. Then he had severe gout in his other knee after finishing one month of colchicine prophylaxis, with documented urate crystals, injected again and responded right away. Of note his repeat uric acid was 4.4. so, (and this is confirmed in studies and in above review), prophylaxis should really be for 3 months, even if the uric acid level plummets as it did in this patient.
    • ​I have seen significant improvements of serum uric acid with decreasing high-fructose corn syrup ingestion: I just saw one of my patients for a routine visit — 77yo man with crystal-proven gout in October 2013, stable CKD stage 3, uric acid level 2 months later was 8.4. He stopped drinking soft drinks completely, and his uric acid decreased over the next 6 months to 7.3, without much other change in lifestyle. He has been now doing more exercise , weight is stable, and uric acid level last week was 6.4. No urate lowering meds. No further attacks of gout. So, anecdotally and based on him and a few other patients, I will continue with pushing an aggressive nonpharmacologic management as my first approach, including the several recommendations above (decrease red meat, alcohol, etc) as well as decrease in sodas and other sources of high-fructose corn syrup (there are some studies I have seen of fructose restriction leading to lowering of uric acid levels, though I have seen nothing on the effects on clinical gout. There are some observational studies: the Nurses’ Health Study found an association between fructose consumption and gouty attacks). Of note, the complete text from AHRQ does include fructose as a risk factor, though no recommendation. and, by the way, coffee and low-fat dairy may be protective
    • I will  continue to inject joints, patient willing (and they all are, in my experience, given the severe pain of gout). My success rate is approx 100% and usually pretty much right away, adverse effects are zero (in my experience), and the patients typically dance their way down the hall  after the injection (especially after injecting a great toe or knee). More in the blog noted above. The full AHRQ report does note that there are no randomized trials done on injections, so not mentioned (though, they do include systemic steroids, where there are also no randomized trials.  Go figure….)

Primary Care Corner with Geoffrey Modest MD: Abrupt vs. Gradual Smoking Cessation

28 Mar, 16 | by EBM

By Dr. Geoffrey Modest

An English study tested two strategies to achieve smoking cessation: a gradual vs abrupt approach (see doi:10.7326/M14-2805). The background is that most guidelines recommend abrupt cessation (“setting a quit date and then stopping cold turkey”), though many smokers report stopping more gradually.

Details of the study:

  • 697 adult smokers (at least 15 cigarettes/d), recruited to quit smoking, choosing a quit date 2 weeks after starting the program. These patients were randomized to either an abrupt cessation program, smoking normally then stopping at the quit date, or a more gradual reduction program, reducing their smoking by daily increments to achieve a 50% reduction by the end of the first week, and a 75% reduction by the end of the second week and then stopping.
  • Both groups received behavioral support from nurses and used nicotine replacement therapy (NRT) before and after the quit date (it is not quite explicit, but I think they all used 21-mg patches in the 2 weeks before the quit date, and those in the gradual group also used short acting NRT such as gum or lozenges. They all used both patches and short-acting NRT after the quit date).
  • Median age 49, 50% male, 94% white, 50% with postsecondary school education, 55% working, 39% lived with a smoker, median prior quit attempts = 2, 20 cigarettes/d, expired CO=24 ppm, median Fagerstrom Test for Cigarette Dependence score = 6 (i.e., highly dependent), 51% preferred gradual cessation and 32% abrupt.
  • Behavioral therapy focused on the commitment to abstain, with early support when withdrawal symptoms are worst/relapse more likely.
  • Nurses saw the patient initially, 1 day before the quit date, weekly for 4 weeks, and finally 8 weeks after the quit date
  • Results, comparing the gradual vs abrupt quit rates:
    • At 4 weeks, 39.2% (34.0-44.4%) vs 49.0% (43.8-54.2%); RR 0.80 (0.66-0.93)
    • At 6 months, 15.5% (12.0-19.7%) vs 22.0% (18.0-26.6%); RR 0.71 (0.446-0.91)
    • Fewer people made a quit attempt (>24 hours of self-reported abstinence) in the gradual cessation group (61.4% vs 71% in the abrupt group; though in the gradual group, they had reduced their cigarette consumption by 48% by the end of the first pre-cessation week (target 50%) and by 68% by the end of the second week (target 75%)
    • ​And, participants who preferred gradual vs abrupt cessation prior to randomization were less likely to be abstinent at 4 weeks (38.3% vs 52.2%)
    • No significant study-related adverse events

So, a few points:

  • This study was done in 31 primary care practices in London. Their explanation for the lack of racial diversity was that the minorities in London tend to smoke much less than the majority white population. But this difference may limit the generalizability of the results to other populations.
  • Those who preferred the gradual cessation method did worse, independent of which group they were assigned to [this is consistent with my practice: very few people who try to cut back gradually do actually achieve abstinence, though very few of them do such a severe reduction program as above, with 75% reduction in 2 weeks]
  • This study raises the issue of starting patches prior to the quit date. In looking at their reference for this (Addiction 2008; 103: 557), this meta-analysis of 4 studies actually showed that patches given 2-4 weeks prior to smoking cessation led to a 2-fold increased long-term quit rate, at both 6 weeks and 6 months. This is not something I have prescribed, though now will do so, 2 weeks prior to the quit date.
  • The people in this study were really nicotine-dependent, and to me their 49% cessation rate at 4 weeks in the abrupt group is very impressive, as is their 22% at 6 months. Especially since smoking an average of a pack a day is not only very addicting physiologically, but involves a pretty extensive amount of time smoking each day, with many more smoking-related associations than those who smoke just a few cigarettes/d (i.e., those who smoke throughout the day may well associate smoking with many different things: waking up, after meals, hanging out with friends, having a beer….), much more so than those who smoke a cigarette on awakening and then after dinner. So, psychologically, heavy smokers also have more cigarette-related associations to deal with in order to quit.
  • I know some clinicians are trying to get patients to cut back to 1/2 ppd (10 cigarettes) prior to setting a quit date, thinking that the overall chances of success would be higher. I am not aware of data looking at this, but this study suggests otherwise.
  • So, I think this data and that of other studies (some but not all) suggest that we push for a more abrupt quit date, ideally with pre-cessation patches (if that is the method chosen). However, as with all of these substance dependencies, there will be many people who are unable to adhere to such a program, and our goal continues to be harm reduction and allowing the patient to determine their own approach to nicotine reduction. And it is important to remember that most smokers take 3-4 quit attempts to finally succeed.

Primary Care Corner with Geoffrey Modest MD: New CDC Guidelines for Opiate Prescribing

25 Mar, 16 | by EBM

By Dr. Geoffrey Modest

The CDC recently came out with their formal guidelines on when to initiate or continue prescribing opiates (see http://www.regulations.gov/#!documentDetail;D=CDC-2015-0112-0002​ ). Of note, it is commented on many times in the publication about the lack of high-quality trials, but that there was an urgency to develop these guidelines given the increasing risks of opioid misuse/adverse effects, and that the “contextual evidence” reviews, complementary information that assists in the translation of clinical research into recommendations, “provides indirect evidence and should be interpreted accordingly”.

 

  1. Nonpharmacologic therapy and nonopioid meds are preferred for chronic pain; and if opioids are used, they should be combined with these interventions as appropriate. There are minimal data supporting chronic opiate benefits, so hard to recommend given their known risks, except for this little caveat in the guidelines: “no study of opioid therapy versus placebo, no opioid therapy, or nonopioid therapy for chronic pain evaluated long-term (>1 year) outcomes related to pain, function, or quality of life. Most placebo-controlled randomized trials were ≤ 6 weeks in duration”. So, no data really. There is a comment that it’s okay for end-of-life care (commenting that “evidence of long-term opioid therapy for chronic pain outside of end-of-life care remains limited”), which does suggest there may be benefit (and, I’m not sure what the real difference in subjective pain is, comparing those at end-of life and those not). My point is that there are basically no data, that in my experience there are patients with really bad chronic pain who pretty clearly benefit from opiates and sometimes higher doses, and this puts us providers in a bind. There is no question to me that trying nonpharmacologic therapy is really important (PT, weight loss in those with knee pain etc., massage/manipulation, psych therapy and esp. cognitive behavioral therapy, exercise…., and combinations of these). And that non-opioid therapies often help (acetaminophen, etc… though I am concerned that prolonged NSAID use has its very real problems for the GI tract, kidneys, and heart especially, and significant mortality), but I should add that some of these drugs (e.g. salsalate, trilisate) are off the Medicare-approved list for unknown reasons, are much more benign, but in my experience sometimes work really well. And local steroid injections often give reasonably long-term relief (e.g. joint injections, trigger point injections) in my experience, as well as other adjuvant meds such as tricyclics, anticonvulsants (pregabalin, gabapentin, carbamazepine), and SNRIs. I would further reinforce avoiding opiates unless really needed, the above often work, and it is clear that opioids do have significant harms (abuse/overdoses, MIs, car accidents…)

 

  1. Before starting opioids for chronic pain, prescribers should establish realistic treatment goals with patients in terms of pain and function, including discontinuing them if benefits do not outweigh risks. This applies to pain lasting >3 months or past the time of normal tissue healing

 

  1. Before starting and periodically during opioid therapy, clinicians should discuss risks and realistic benefits of continued use, as well as the patient and provider responsibilities for managing therapy. This includes safety issues, which might be uncovered by looking at the prescription drug monitoring program (PDMP). Again, the issue is: unknown benefit (i.e., not studied, though the patient may attest to the benefit) but clear risks (and there are data showing that patients who have multiple providers prescribing the opioids are at increased risk). And contextual evidence suggest that many patients do not understand the safety issues.

 

  1. When starting opioids, use immediate-release ones, not the extended-release ones. The latter have likely increased potential for overdose, and, as I have mentioned in earlier blogs, there really are no data showing that long-acting ones are better, either more effective or safer. Also, if you decide to switch from short to long-acting and are switching opioids, remember that there is incomplete cross-tolerance, so the dose of the long-acting med should be reduced. Also, given the above, they recommend NOT giving long-acting along with short-acting opiates (this is pretty different from the old model: give long-acting to get steady state of opiates, then short-acting for “breakthrough” pain). Also given the [actually not-so-scientific] data finding more deaths with methadone, that should not be the first agent to use for a long-acting one.

 

  1. Use the lowest effective dose of opiates. And especially if increasing the dose to >50 morphine milligram equivalents (MME)/day. And generally “should avoid increasing the dosage to ≥​​ 90 MME/day”. One interesting contradiction is that methadone maintenance programs often have people above 100mg methadone/day (that is, >300 MME) for the long-term. In fact I have a chronic pain patient who is in a methadone program and on 70mg for the past many years. Given the presumed benefit of TID dosing of methadone for chronic pain, I appealed to the Medicaid program in Massachusetts so I could give him 70mg of methadone in divided doses at the health center but was unable to get approval for more than 60mg, the Medicaid max. However, I was told I could give him 60mg of methadone and an almost unlimited amount of oxycodone along with it (?!?). The dosage restriction suggested above, as pointed out in prior blogs, comes from ecological data showing that those on higher doses (e.g. >100 MME/day) have higher risk of overdoses and deaths. But, again, there are NO (as in, zero) randomized controlled studies looking at the benefits of higher vs lower doses. And I certainly have some chronic pain patients who are on high doses for a long time and who are very willing to take risks in order to get “better pain relief and function”, from their perspective (part of the issue in those requiring higher MME’s is that they may have genetic variants in mu receptors and need higher doses to get an effect– see past blogs as listed at the end). Also, we should consider giving naloxone kits to patients on opioids in case there is an overdose, esp. if they are on higher doses of opiates.

 

  1. Chronic opiate use begins with acute pain therapy. We should also give the lowest dose possible and shortest duration of immediate-release opiates. (And ERs should not blithely prescribe opiates). “3 days or less will often be sufficient; more than 7 days will rarely be needed”. The 3-day suggestion is largely “expert opinion”, though there was a study in patients with acute low back pain showing that there was usually a significant decrease in pain by the 4th day. And another one I blogged on recently (see blogs below) not finding that opiates were in fact better than nonopiates for acute low back pain. And the guidelines reinforce not giving ER/LA preparations for acute pain.

 

  1. Evaluate benefits and harms within 1-4 weeks of starting opiates and at least every 3 months thereafter, more frequently if a history of substance use disorder, of overdose,  if taking ≥​​ 50 MME/d, or if taking other CNS depressants. There may be utility to using validated scales to assess function, pain control and quality of life (e.g. PEG scale–Pain average, interference with Enjoyment of life, and interference with General activity). The recommended rate of tapering doses is not clear, some suggesting rapid tapers over 2-3 weeks in those with severe adverse events (e.g. overdose), others recommend slower tapers at 10%/week.

 

  1. Before starting and periodically thereafter, evaluate risk factors for opioid-related harms. Include considering offering naloxone
  • Patients with disordered breathing: the issue is opiate-related respiratory depression. Those with moderate-to-severe sleep-disordered breathing should probably not have opiates
  • Pregnant women: avoid initiating opiates during pregnancy, since they are associated with stillbirth, poor fetal growth, pre-term delivery, neonatal opioid withdrawal syndrome and birth defects. And for those pregnant and on opiates chronically, be careful about tapering (risks to patient and fetus if patient goes into withdrawal). Also a potential issue with breast-feeding: neonatal toxicity and death have been reported when mothers take codeine
  • Patients with renal or hepatic insufficiency — use more caution and increased monitoring, given decreased processing/clearing of drugs
  • >65 yo: opiates may be more dangerous, given reduced renal function. Also, more opiate-related confusion.
  • Mental health issues: untreated depression could lead to overdoses (suicide, or confusion). Anxiety treated with benzos adds toxicity when given together with opiates. And, though not mentioned in the recommendations, those under stress or not sleeping well experience more pain (i.e., best to try to help with underlying issues here)
  • Patients with substance use disorders — illicit drugs and alcohol increase likelihood of opioid-related overdose deaths
  • And, consider giving naloxone to those who are at higher risk of overdose

 

  1. Review the PDMP to see if patient is receiving high dose opiates or other meds that put him/her at higher risk. This should be done at least every 3 months. (Though I would add that there are a few problems here: the pharmacy data are not updated as quickly as they should be; navigating the website is not easy and one has to click on the same patient many times if they list different addresses; hard to get data on patients who go to other states for opiates or gets them through the VA system; and it really takes a lot of time doing so in a busy primary care session (the issue of chronic pain management really is, to me, the poster-child for team-based care: a clinician just does not have the time to do everything, especially since we typically have so many complex medical and psychosocial issues to take of in mostchronic pain patients. A team-approach with nursing and others involved in the voluminous paper work, checking PDMP, calling patients back for urine tests/pill counts, etc., is really essential to practicing high quality care).

 

  1. Check urine drug screen prior to starting opiates, and “consider” doing them at least annually thereafter. These are important for a variety of reasons, including patient safety

 

  1. Avoid prescribing opiates if patients are on benzodiazepines. Based on a lot of observational data, but as pointed out in some prior blogs, those on benzos by themselves may have underlying psych conditions which have significant mortality associated. But the opiates and benzos in combo are likely to produce more respiratory depression. In stopping the benzos, very important to taper slowly (e.g. decrease dose not more than 25% every 1-2 weeks)

 

  1. Arrange treatment for patients with opioid use disorder (e.g. with methadone or buprenorphine as meds; in combination with behavioral therapies). I believe that all of us who prescribe buprenorphine are very impressed with the results in the majority of patients… I really feel it is one of the few interventions I do which really give patients back their lives. And, given the huge benefits and significantly decreased risks of buprenorphine, I can see no reason why nurse practitioners/physician assistants/medical residents should not be able to prescribe buprenorphine, both because it is so effective in so many people, and, also, ironically, these providers are allowed to prescribe much more potentially dangerous meds anyway (oxycontin, methadone etc.)

 

So, my bottom line is that there is no doubt that opioids can be dangerous both to the patient and society (through diversion, availability in the streets, overdoses, crime), with cited statistics of 165,000 people dying from overdoses related to opioid pain medication in the US from 1999-2014, and >420,000 ED visits related to opioid pain relievers in 2011. And this danger is very likely increased with higher doses of opiates, or their combos with other meds (e.g. benzos). But there really are very little scientific data to inform these guidelines, making it hard for us in the trenches to accept the “expert opinion” when we have patients in front of us with inadequately treated chronic pain and severe functional impairment from that pain. And, I think, pain is pain, whether it is in cancer patients, those at the end-of-life, or those who fall off a ladder. So, I am a strong advocate for pretty much all of the above guidelines, especially trying to avoid opiates whenever possible, using adjunctive therapies including injections, trying to avoid benzos, giving the lowest opiate dose possible, educating patients on risks and benefits (And emphasizing that the benefit of opiates is rarely complete or near-complete pain relief). And I have even had several patients come off chronic opiates, some having been on them for years. But, there is no question in our practice, this issue of treating chronic pain is remarkably common and remarkably difficult (and remarkably hard to do in the context of a brief primary care visit, where we also deal with their depression/psych issues, hypertension, homelessness or other profound social issues, diabetes, illicit drug use, domestic violence, ……..). And there is no question to me that some patients do need higher doses of opiates to function, whether they have cancer or not.

 

A couple of other comments on the guidelines:

 

  • The estimates of the risk of opioid addiction are lower than previously believed/promulgated: in pain clinic settings, the rate of addiction is 2-14%. In primary care settings in patients on chronic opioids it is 3-26%.
  • Although methadone has been singled out as a particularly bad actor, and now requires more stringent prior authorization by Massachusetts Medicaid, the actual data are not so clear: several observational studies (e.g. Oregon Medicaid) found no increased risk of death or overdose, and a VA study found lower overall risk with methadone, despite the concern about prolongation of QTc intervals. another recent study did find increased risk of overdose with methadone, with “twice as many single-drug deaths as any other prescription opioid”

 

For other blogs:

http://blogs.bmj.com/ebm/2015/11/10/primary-care-corner-with-geoffrey-modest-md-prescribed-opioids-and-future-prescription-opioid-misuse-in-teens/ shows that teens given legit prescribed opiates are more likely to misuse opiates later in life. There are also studies in adults having cataract surgery or varicose vein stripping, finding that those still using opioids within 7 days of surgery had higher risk of use after 1 year (cannot show causal relationship in this type of study, but does raise the potential benefit of avoiding or minimizing opioid use unless absolutely necessary, even for short-term acute pain)

http://blogs.bmj.com/ebm/2015/11/06/primary-care-corner-with-geoffrey-modest-md-opiates-for-acute-low-back-pain/ finding unclear benefit of giving opiates

http://blogs.bmj.com/ebm/2015/06/17/primary-care-corner-with-geoffrey-modest-md-mass-med-society-opioid-prescription-guidelines/ which includes many of my comments about the lack of studies on opiates and the risks of developing strict guidelines in their absence (many more comments than above)

http://blogs.bmj.com/ebm/2015/03/16/primary-care-corner-with-geoffrey-modest-md-feel-good-gene/​ which looks at some genetic variants (e.g. in the mu receptor) and their effects on individual’s drug use

Primary Care Corner with Geoffrey Modest MD: Atrial Fibrillation and Lower BP

24 Mar, 16 | by EBM

By Dr. Geoffrey Modest

Although there have been many studies confirming a role of hypertension in the development of atrial fibrillation (AF), a secondary analysis of the LIFE trial gives insight into the effects of achieving different levels of blood pressure on the frequency of development of AF (see Hypertension. 2015;66:368). The LIFE trial (Lancet. 2002;359:99) used 2 different hypertensive agents (losartan and atenolol) in patients with EKG-documented LVH to assess differences in clinical outcomes.

Details:

  • 8831 hypertensive patients (mean age 66.6, 45% male, 6% Black race, 13% with diabetes, 18% ischemic heart disease, 7% MI, 5% stroke, 15% smokers, BMI 28), with EKG LVH and no history of AF, in sinus rhythm on baseline EKG, were randomly assigned to losartan or atenolol, and followed 4.6 years
  • Patients with in-treatment achieved SBP ≤ 130 mmHg (lowest quintile at last measurement in the study) were compared to those with SBP 131-141 vs those with ≥​142

Results:

  • New onset AF developed in 701 patients (7.9%)
  • In multivariate analyses (controlling for age, sex, race, DM, history ischemic heart disease/MI/heart failure, serum glucose/creatinine/microalbumin, prior BP therapy), comparing achieved SBP of ≥​142 mmmHg:
    • Achieved SBP of ≤​130 mmHg was associated with a 40% lower risk of AF (18-55%, p=0.001)
    • Achieved SBP of 131-141 mmHg was associated with a 24% lower risk of AF (7-38%,  p=0.007)
  • ​For each 10mmHg decrease in SBP:  13% lower risk of AF (9-17%, p<0.001)
  • ​And, no difference in benefit of lower SBPand AF in those > or <60yo
  • But, lowering SBP to ≤125 mmHg was no longer associated with reduced risk of AF (all achieved SBPs less than 125 were nonsignificantly related to the development of AF, though the hazards ratio trended to increasing risk with progressively lower SBP)

So, a few points:

  • Although the LIFE cohort included only patients with LVH on EKG, it has the advantage of using 2 different BP meds with 2 different mechanisms of actions. This makes it more likely that it is the achieved blood pressure which correlated with the development of AF. (With only one medication, one might wonder if the association was the blood pressure lowering effect or perhaps some other unrelated effect of the med).
  • But, one concern here is that those on losartan had somewhat lower likelihood of developing AF (in those who developed AF, 46.2% were on losartan vs 50.6% on atenolol). And we know from the LIFE study that those on losartan had more regression of their LVH than those on atenolol, and this was the purported reason that in the overall LIFE trial there were overall fewer cardiac events in the losartan group. In fact, the incidence of cardiac events in the LIFE study overall was equivalently lower in both the losartan and atenolol groups when there was regression of LVH, but regression was more common in the losartan group. So, it may be that looking at the post-hoc analysis of hypertensive patients with LVH and their likelihood of developing AF might not be so generalizable to hypertensives without LVH (.e., if the development of AF were at least partly related to LVH on EKG).
  • Prior articles have had somewhat mixed results: the Cardio-Sis trial (Lancet. 2009;374:525) found statistically fewer cases of new onset AF in those on tighter control (achieved SBP of 131.9 mmHg was better than 135.6), though another study did not (Am J Hypertens. 2008;21:1111)
  • So, this trial adds to the argument that more dramatic lowering of the blood pressure may have another positive effect: decreasing the likelihood of developing AF. And, of course, this is a really important clinical endpoint (stroke, other emboli, risks of prolonged anticoagulation and/or cardiac procedures, risk of sudden cardiac death and heart failure, risk of cognitive decline, …). though there were also limitations of the SPRINT trial (see http://blogs.bmj.com/ebm/2015/11/19/primary-care-corner-with-geoffrey-modest-md-tighter-blood-pressure-control-the-sprint-trial/​ , which did not include diabetics but did find a pretty much all-endpoint benefit of tighter control at an achieved SBP of 121 mmHg), this current study does add to the literature suggesting more aggressive goals of therapy, with SBP target in the 125-130 mmHg range, at least in those with EKG-LVH. Though, it should be added, that this study had too few diabetics to make a meaningful argument about their blood pressure goal, and another recent blog (see http://blogs.bmj.com/ebm/2016/03/07/primary-care-corner-with-geoffrey-modest-md-hypertension-goal-in-diabetes/ ) assessed a systematic review finding that the goal for diabetics should perhaps be higher than others, with a target of 140/75-80. And I will add my usual caveat to be less aggressive with elderly, since postural hypotension/risk of falls is so common(?autonomic dysfunction, see http://blogs.bmj.com/ebm/2014/12/18/primary-care-corner-with-geoffrey-modest-md-orthostatic-hypotension/) and too low a blood pressure can be associated with cognitive decline (see http://blogs.bmj.com/ebm/2015/04/23/primary-care-corner-with-geoffrey-modest-md-too-low-blood-pressure-and-cognitive-decline-in-elderly/ ).

Primary Care Corner with Geoffrey Modest MD: Microbiome Changes and Severity of NAFLD

18 Mar, 16 | by EBM

By Dr. Geoffrey Modest

There is not a great understanding as to which patients with non-alcoholic fatty liver disease (NAFLD), the most common liver disorder in the US/Western countries, are among the 20-30% who progress to nonalcoholic steatohepatitis (NASH), or those who progress even further to fibrosis and cirrhosis. Certain genetic polymorphisms have been identified which predispose people to more aggressive disease: there are some data that the I148M variant of the PNPLA3 gene confers a 3.5-fold increased risk of NASH and a 3.2-fold increased risk of fibrosis. And there may be roles for epigentics, gender/hormone status, and nutrition as well. This article looked at the potential role of the gut microbiome (see HEPATOLOGY 2016;63:764), since as noted in several blogs (see below), there may also be a role of microbiome changes in some related conditions (e.g., obesity, metabolic syndrome, diabetes).

Details:

  • 30 patients with no/only periportal F0/F1 fibrosis (10 with NASH) and 27 patients with significant F≥2 fibrosis (25 with NASH) had 16S ribosomal RNA gene sequencing of stool samples. All patients had liver biopsy diagnosis, did not drink alcohol >210 g/week for men or >140 g/week for women, did not have chronic hepatitis B or C, and did not have evidence of other chronic liver diseases on biopsy.
  • Mean age 57, 34 males/23 females, BMI 31, 40% with diabetes, 50% elevated triglycerides, 75% depressed HDL, 81% with metabolic syndrome, mean AST of 40 and ALT of 64.

Results:

  • Bacteroides was significantly more abundant in those with NASH and F≥2 fibrosis; Prevotella was decreased (these two genera are competitors with an inverse abundance relationship). Also, Ruminococcus  was increased.
  • On multivariate analysis (adjusting for BMI, BP, triglycerides, HDL, metabolic syndrome), Bacteroides was independently associated with NASH, and Ruminococcus with F≥2 fibrosis.
  • ​There was a dose-response curve: both the rate of NASH and F≥2 fibrosis tracked with increasing abundance of Bacteroides and Ruminococcus, respectively
  • ​In the subgroup with metabolic syndrome (overall a group with higher risk of more severe NAFLD lesions), those with more abundant Bacteroides and Ruminococcus had more severe NAFLD lesions. This was also found in those with diabetes and several of the components of metabolic syndrome
  • In assessing the presumed functional effects of these bacterial changes, those with NASH had a microbiome enriched in ability to metabolize carbohydrates, lipids, and amino acids.
  • This study adds to the potential role of microbiome changes in causing clinical diseases. The study itself cannot imply causality, just an association: for example, did the microbiome cause the changes in the microbiome, or vs vice versa? Were there other nonetiologic factors that caused both the microbiome changes in these patients and the NAFLD/NASH changes in the liver,such as eating too much pâté (this was a French study, after all)? But, arguments in favor of the microbiome changes being causal:
    • Animal studies show that manipulating the gut microbiome can lead to changes in the liver lesions of NAFLD, including steatosis, NASH, fibrosis and liver cancer
    • ​Bacteroides is associated with increased fecal content of deoxycholic acid, D-pinitol, choline, farrrinose, and stachyose (the last 2 containing glucose and fructose), and lower amounts of short-chain fatty acids (SFCAs) and amino acids. And deoxycholic acid induces apoptosis in the rat liver and is increased in NASH patients, fructose is associated with increased liver inflammation and fibrosis in NAFLD patients, and decreased SCFAs (esp. butyrate, propionate and acetate — see Curr Opin Clin Nutr Metab Care 2014, 17:139) may be detrimental to NAFLD
    • Bacteroides is favored overall in the gut when people eat western diets (high in fat, animal proteins, and sugar), vs Prevotella being favored in those eating foods rich in fiber, starch and plant polysaccharides. In fact changing the diet to an animal-based one leads to a rapid shift in the gut microbiome to Bacteroides, and promotes insulin resistance.

So, what are the implications of this study:

  • This study and others on the microbiome (for example, see blogs: http://blogs.bmj.com/ebm/category/microbiome/​ ) reinforce that there seems to be a dynamic interrelationship between the gut microbiome and human disease, and that the changes in the microbiome lead to changes in bacterial metabolism and byproducts, which may be the mediators/abettors of disease processes.
  • There are several key players affecting the composition of the gut microbiome, including diet [see above microbiome blogs for articles on red meat and heart disease, medications (including one on metformin suggesting that much of its hypoglycemic role is as a promoter of healthy changes in the microbiome) as well as on antibiotics, and exercise]
  • And, I think that the associations with NAFLD above (even if not clearly causal) will expand my approach to patients with NAFLD to include reinforcing a vegetable-based diet, as well as my usual approach of weight loss, lipid control, and exercise.

Primary Care Corner with Geoffrey Modest MD: Low Back Pain Treatment per AHRQ Review

17 Mar, 16 | by EBM

By Dr. Geoffrey Modest

The agency for healthcare research and quality (AHRQ) just published an evaluation of the literature on noninvasive treatments for low back pain (LBP), looking at both pharmacologic and nonpharmacologic approaches (see https://www.effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=2192 ).

Details:

  • As we know only too well, LBP is really common. 84% of adults will have LBP at some time, and >25% have had it within the past 3 months
  • 1998 US health care expenditures were $90 billion, not including the rather large indirect costs of lost work productivity, etc.
  • Those with acute LBP (up to 4 weeks) typically have rapid improvement. Those with subacute (4-12 weeks) tend to have slower improvement, and those with chronic (>12 weeks) often do not get much more improvement and account for much of the costs of LBP treatment
  • Predictors of chronicity: psych comorbidities, maladaptive coping strategies (e.g. fear avoidance: avoiding activities because they fear they will make things worse), catastrophizing (e.g., anticipating the worst possible LBP outcome), presence of nonorganic symptoms (without physiologic basis), high baseline functional impairment, and low general health status. [By the way, we used to suggest that people with low back pain have strict bedrest, to the point of using urinals at the bedside, for 1-2 weeks. This was subsequently found to be incorrect and counterproductive/harmful, and I would imagine would reinforce the “maladaptive coping strategies” noted. I wonder if we created more chronic LBP by our older incorrect advice???]
  • Imaging: big issues of false attribution — degenerative changes, facet joint arthropathy, bulging or herniated discs are really common in people with and without [And, in my experience, I have had several patients with very severe lumbar spinal stenosis both by symptoms and by really awful looking MRIs, who have spontaneously gotten dramatically better, in a few cases becoming asymptomatic without any treatment]
  • 156 publications met the inclusion criteria of AHRQ, most in patients with nonradicular LBP
  • Results:
    • Pharmacologic therapies:
      • Acute and subacute LBP:
        • NSAIDs, opioids (only studied: buprenorphine patch), and skeletal muscle relaxants were associated with small effects on pain (vs placebo).
        • NSAIDs were associated with small effects on function
        • Acetaminophen and systemic steroids had no benefit vs placebo
      • Chronic LBP:
        • NSAIDs and tramadol had moderate effects on pain, vs placebo
        • Opioids, duloxetine, and benzos had small effects on pain
        • NSAIDs, opioids, tramadol, and duloxetine had small effects on function
        • Tricyclics had no effect (though older studies did show small benefit), and there were not enough data to determine if gabapentin on pregabalin helped; evidence was inconsistent on opioids vs NSAIDs
      • Radicular symptoms
        • Limited data, but no difference in pain or function with systemic steroids vs placebo. One study found that benzos delayed return to work. Insufficient evidence for gabapentin or pregabalin
      • Harms of therapies: overall not very well reported
    • Nonpharmacologic therapies: (limited studies overall)
      • Acute LBP
        • Spinal manipulation, heat, massage, low-level laser therapy are associated with some benefit vs sham treatments or no intervention/usual care
        • Exercise, massage, and heat had moderate effect on pain and function
        • The data on using ice/cold packs is insufficient for a recommendation [though, in my experience, many patients do find it helpful]
      • Chronic LBP:
        • Exercise, yoga, tai chi; psychological therapies (especially restoration or cognitive-behavioral therapies); multidisciplinary rehab; acupuncture; spinal manipulation; and low-level laser therapy have small to moderate effect for improving pain or function
      • ​Evidence for taping, electrical muscle stimulation, passive physical modalities had too little data; one study on ultrasound or TENS showed no benefit vs sham ultrasound/TENS

So, these assessments raise several issues:

  • Systematic reviews and meta-analyses have one really large limitation: they only include those studies which were actually done. I.e., even though some meds may work, or different doses of meds than those studied may work, they get no support in the review if they were never tested in a formal study. And, for better or worse, much of what we do in medicine does not have the support of rigorous studies.
  • In the studies included in the systematic reviews (which include onlymethodologically “good” studies), several may yield the “no benefit” designation if the drug was no better than placebo. But many placebos get reasonable responses, on the order of 20-30% often, so suggesting acetaminophen, for example, has helped several of my patients feel better and be able to function through perhaps the very real “placebo” effect (for more on the placebo effect, see http://blogs.bmj.com/ebm/2015/05/07/primary-care-corner-with-geoffrey-modest-md-placebo-genetics-and-the-placebome/ for a discussion of the genetics, or http://blogs.bmj.com/ebm/2014/11/18/primary-care-corner-with-geoffrey-modest-md-placebo-for-coughs-in-kids-and-an-adult-perspective/​ for a couple of examples).
  • One currently very hot topic is the use of opioids for chronic low back pain. And it is a really important issue given their attendant huge social costs (addiction, overdoses, etc.) and is particularly relevant given the large numbers of people on chronic opioids for chronic LBP (one of the most common reasons for chronic opioid prescribing). But for acute low back pain, there are only 2 studies (of “low” stength-of-evidence), using only buprenorphine patches and showing a small effect on pain relief. And only 4 studies showing moderate effect on the pain of chronic LBP. I’m not sure how that squares with several of my patients who derive significant benefit even though I really have no doubt that they are taking the meds regularly and have real, functionally-disabling pain that we are treating. And there are no really good trials looking at opioids vs NSAIDs or other drugs, or even what dose of opioids is adequate for pain relief
  • More invasive procedures were not included in this review. And, for example, well-designed studies suggest that epidural injections do not help radicular back pain. But I have certainly had several patients who were in constant pain and unable to function well, who have gotten very dramatic and durable relief from injections. Is that a placebo effect?? Maybe. But it really restored function and basically eliminated their pain, so I will continue to prescribe it when all else fails, and typically before a referral for surgery

So, as with many medical papers, this one sheds some light but largely raises the many lacunes in our knowledge base, ones that we really need answered to practice high quality, appropriate care. (I hate to say the usual caveat after pretty much all editorials in the major medical journals, but “further studies should be done….”)​

Primary Care Corner with Geoffrey Modest MD: Further Drug Maker Shenanigans, and Direct-to-Consumer Advertising

16 Mar, 16 | by EBM

By Dr. Geoffrey Modest

The NY Times had yet another expose on drug companies, this time perhaps setting a really bad precedent for the FDA (see http://www.nytimes.com/2016/03/09/business/fda-deal-allows-amarin-to-promote-drug-for-off-label-use.html?_r=0​ ). In this case a drug company sued the FDA to be able to market a triglyceride lowering agent without an approved indication. Details:

  • Background: the FDA has a long-standing policy that drug companies cannot market drugs for off-label indications, and in recent years drug companies have paid billions of dollars in fines for doing so.
  • The drug company (Amarin, which has only this product) had FDA approval in 2012 to market its fish oil variant Vascepa [icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA)]​, to patients with triglycerides > 500 mg/dL. They subsequently wanted the right to market this drug to a much broader range of patients with lower triglyceride levels, without clinical trials showing documented benefit, stating that it was their first amendment right to advertise “truthful information to promote its drug”, and a district judge in Manhattan agreed. the FDA backed off and agreed to let Amarin use their “free speech” to promote this drug
  • The FDA downplayed the implications of this action, stating that this was a narrow ruling, applying only to this case, and that their general approach has not changed.
  • But, as quoted, Dr Michael Carome, director of health research at Public Citizen, a consumer advocacy group: “This really sends a signal to other companies that if you want to engage in off-label promotion, you can negotiate with the FDA”

So, this brings up a few issues:

  • Clearly, this type of lawsuit is quite troubling, allowing the drug company to promote a drug without FDA-approval but based on a judge stating this is “free speech”. Drug companies naturally see it as in their financial interest to broaden marketing by adding on indications for drugs as much as they can. And they are likely to use their own sponsored studies to document benefit as “truthful information” for the clinicians and patients to go on. As noted in a myriad of blogs over the past 5 years (see below), there are many drug companies that will do pretty much anything to increase their markets. so, one issue is the legitimacy of all of these drug-company sponsored studies (clearly, there are many important studies sponsored by drug companies that appropriately influence medical practice. but there are also many documented sleazy studies, where drug companies have not allowed access to the data, where negative studies have been squelched and not published, etc. again, lots of examples in the blogs.)
  • The Vascepa case, on my review, shows that the FDA based its original approval on a 12-week study in patients with fasting triglycerides between 500-2000 mg/dL, only showing a decrease in triglycerides. The FDA accepted this use of a surrogate endpoint (lowering triglycerides when they are very high) because of the known bad effects of very high triglycerides and with current guidelines suggesting treatment of such high levels [the best data are for the association of high triglycerides (>500, and esp >1000 mg/dL) and pancreatitis. the data on the relationship with coronary artery disease is pretty complicated and uncertain, to my reading]. So, extending the recommendation to those with lower levels of hypertriglyceridemia is a bit of a stretch. Of note, even for the higher levels of hypertriglyceridemia, there is a disclaimer in the drug labeling noting “the lack of evidence that treatment with Vascepa reduces the risk for pancreatitis in patients with severe hypertriglyceridemia”.
  • So, the real concern is the slippery slope. The ability of this drug company to get the FDA to bend, based on the rather spurious argument (to me) that it is free speech (though there is really ZERO scientific evidence showing that there are improved clinical outcomes, only drug-company innuendo), really does open the door for the FDA being stripped of its regulatory, consumer-protective role.
  • Also, there was an interesting report by STAT on drug company direct-marketing to the consumer (see http://statnews.com/2016/03/09/drug-industry-advertising/ ). It turns out that:
    • ​Drug companies are spending $5.2 billion in 2015 (70% on TV ads) on direct-to-consumer advertising, growing dramatically each year (was $4.3 billion last in 2014). These numbers do not include hundreds of millions spent on digital and social media ads.
    • ​1/4 of advertising was for 5 drugs: humira (adalimumab, used in several inflammatory diseases), lyrica (pregabalin, for neuropathy etc.), eliquis (apixaban, a “novel” anticoagulant, see below for link to blogs critiquing them), cialis (tadalafil, used for erectile dysfunction), and xeljanz (tofacitinib, used for rheumatoid arthritis); all really really expensive and need to be taken for a very long time for continued efficacy.
    • 9 drugs this year are on  schedule to break $100 million/drug  in TV ads (e.g. Harvoni, for hepatitis C)
    • Of note, only the US and New Zealand are the only countries allowing direct-to-consumer advertising
    • The AMA has called for a ban on this direct-to-consumer advertising
    • And, shockingly to me (but perhaps I should not be surprised), drug companies get tax breaks for these ads; Senator Al Franken and others have introduced bills to eliminate these tax breaks, mostly based on the fact that these really expensive drugs add to the exorbitant costs of health care, and probably should not be subsidized by the populace….

See http://blogs.bmj.com/ebm/category/pharmacy/ for several blogs on drug company malfeasance, including several on the novel anticoagulants, poor drug company compliance in reporting mandated data to the FDA, and even an earlier one (9/10/15) looking at Vascepa and with a review of FDA history

Primary Care Corner with Geoffrey Modest MD: Latent TB Infections: Screening and Treatment and Probs with IGRAs

15 Mar, 16 | by EBM

By Dr. Geoffrey Modest

The USPSTF just circulated a draft recommendation for screening for latent TB infection (LTBI) — see http://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement144/latent-tuberculosis-infection-screening​ . In brief, they are recommending that adults “who are at increased risk for TB” be screened, grade B recommendation (high certainty that net benefit is moderate).

Details:

  • The 2011-12 National Health and Nutrition Examination Survey estimates the prevalence of LTBI in the US at 5% (worldwide, about one-third of the world’s population is infected with TB, with 1.5 million deaths in 2014. in the US there were 555 deaths in 2013)
  • 30% of those exposed to Mycobacterium TB develop LTBI; of these, 5-10% progress to active TB disease
  • Those at increased risk for TB: born in or were former residents in countries with increased TB prevalence, or have lived in high-risk congregate settings (e.g., homeless shelters, correctional facilities)
  • In 2014, 66.5% of active TB infections were among foreign-born, with 13.4x the incidence of US-born
  • ​>50% of foreign-born with active TB were from: Mexico, the Philippines, Vietnam, India and China. The CDC also adds Haiti and Guatemala to the list of high risk.
  • In those >15 yo with active TB, 5.5% were homeless within past year, 2.2% were in long-term care facilities, 4.2% in correctional facilities at time of diagnosis
  • Estimates of those with LTBI by TST (Mantoux tuberculin skin test): 23.1-87.6% of prisoners and 18.6-79.8% of homeless
  • Those in health care settings may also be at higher risk of infection and may be an important site for TB surveillance
  • And, the subgroup who are much more likely to develop active TB from LTBI: immunosuppressed [including HIV, those on immunosuppressives (including those on TNF-a inhibitors, and those receiving organ transplant) and silicosis]. They did not comment on other common subgroups: those with renal failure, diabetes, on prednisone >=15mg/d for one month, and I would consider testing for LTBI in all of these groups and treating if positive.
  • Screening can be done by either TST or one of the IGRA assays. Both are supported by the CDC (for full updated CDC guidelines from 2010, see http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm?s_cid=rr5905a1_e ). But see below blog from July 2014 for my concerns about the IGRA tests.
  • Benefits of detecting LTBI: adequate evidence that treating LTBI with one of recommended CDC regimens decreases progression to active TB
  • Harms: primary harm is hepatotoxicity
  • Screening intervals: unclear
  • Treatment: as per CDC guidelines

So, a few points:

  • I work in a community with a pretty high prevalence of TB exposure, BCG use, and also with several cases of active TB over the years (mostly in older people, perhaps from waning immune systems). One of our big issues is interpreting the TST in those with BCG exposure. The reality is that we do not have an exact method, since there is no gold standard for the diagnosis of LTBI. And I do not trust the new IGRA tests, though on paper they make a lot of sense especially in the subgroup who received BCG immunization (see the blog below for details of 2 rather disturbing studies, suggesting that the IGRA results are not stable and therefore not completely reliable). Unclear why they are unstable. perhaps different numbers of interferon-g-producing T cells in the periphery, perhaps reversion to normal from a positive reflects that the immune system cleared the TB infection, maybe technical errors in performing the assay, or the definition of a positive IGRA may be too lenient (see articles below)
  • I have been prescribing the CDC-recommended rifampin-based treatment in patients who are not concurrently on meds that interact badly with rifampin, a strong CYP3A inducer. The rifampin regimen is shorter (4 months, vs 6-9 months for INH) and has significantly less hepatotoxicity

For some reason, the blog from July 2014 did not make it onto the BMJ website, so I will reprint it below:

A recent article found the disturbing result that the Interferon-γ release assays (IGRAs) For tuberculosis seems to have many false positive results (see DOI: 10.1164/rccm.201305-0831OC). This is particularly disturbing since many institutions (including some of the most prestigious hospitals) rely heavily or exclusively on IGRAs [70 have adopted QuantiFERON-TBGold (QTF)]. I sent out a blog a couple of years ago questioning the validity of IGRAs at the Cleveland clinic (see below). The current study is more impressive and with larger numbers of health care workers. For background reference, MMWR did a full issue on PPD vs IGRAs in 2010 (see http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf. ). There was some concern voiced to me by a TB specialist member of the CDC committee involved in producing this paper at that time, stating that most of the committee members voicing approval for IGRAs (not including him) were receiving funding from producers of the tests, and that he felt that there was insufficient data to endorse IGRAs at that time. (Of course, one of the issues is that there is no good gold standard – the comparison is with PPDs, which can have false pos and neg results). The current study was at Stanford (which adopted serial QFT screening in 2008, with more than 10,000 employees).  Baseline at Stanford:

  • 611-bed hospital with mean of 14 cases of pulmonary TB/yr between 2006-2011
  • Surrounding community with estimated TB rate of 10.7-10.9 cases per 100K people
  • From 2008-2010, all employees were screened annually with QFT, independent of prior PPD status or if had received therapy for LTBI (latent TB infection)
  • Analyzed 9153 health care workers with at least 2 results over time from QFT, 72% female, man age 43

Results:

  • Overall 13.9% of QFT tests were positive
  • Of 1223 individuals initially with positive QFT,5% remained positive (“persistently positive”)
  • Of 8227 initially negative, 4.4% converted to positive (which was 11x the rate of prior conversions with PPDs!!)
  • Of those whose QFT reverted from positive to negative, 73.9% had titers between 0.35 and 1.0 IU/ml (0.35 being the cutoff value for positive), vs that titer in 62.4% going from negative to positive and 27.8% of persistently positive
  • Of the 361 workers who converted to positive, repeat testing was done in 60 days in 261 of them and 8% reverted to normal.
  • In 16 low-risk workers with conversions from negative to positive who were persistently positive after the repeat test, 12 (75%) reverted ultimately to negative
  • If change cutoff for positive increased to be 1.0 IU/ml, that would eliminate 67% of discordant repeats, but fail to pick up 33.7% of persistently positives
  • And one interesting analysis: if one were to assume that the PPD conversion rate at the institution (0.4%) were a true reflection of LTBI (and it has the longest track record with such repeat testing), that would translate to a QFT cutpoint of 5.3 IU/ml to get the same 0.4% conversion rate. In that case the persistent positive QFTs (who presumably have the highest likelihood of real LTBI) would be reduced by 68.6%

So… one would have thought (including me) that this more specific test (the IGRAs) would be great, esp for those of us working in communities with a high prevalence of prior BCG vaccination and a moderately high rate of TB. This article is pretty impressive in demonstrating the variability of QFT results. Not sure if this applies to other IGRAs (the MMWR considers the QFT and T-SPOT as pretty equivalent), or if QFT would really be more accurate with a higher cutoff value for positive (again, hard to assess directly since there is no great gold standard. and, would one then miss a lot of true positives??). Also would have been interesting to know what % of workers at Stanford with positive PPD had negative QFT, but this was not reported in this article. Bottom line: probably best to stick with PPDs as the test-of-choice

An additional blog was circulated in 2012, prior to the BMJ blogs, finding false positives in the Cleveland Clinic (see Chest 2012; 142: 55). In this retrospective chart review of health care workers from 2007-2010, these workers had received the QuantiFERON-TB Gold test. In very brief:

  • 7374 IGRAs were done on newly hired health care workers
  • 486 (6.6%) were positive at baseline 305 (4.1%) were indeterminate and 6,583 (89.3%) were negative
  • Serial IGRAs were done and detected 52 (2.8%) who converted to positive (mean value of 0.63 IU/ml, 29% with values >1). [Note that the baseline conversion rate for TST prior to IGRA testing was 0.09%, though there may have been people who did not return for TST readings]. for the converters:
  • 41% had a history of BCG immunization
  • None were part of documented TB outbreak
  • 43 of these 52 had further evaluation an 26 (61%) got INH therapy
  • 10 who did not get the INH (including one with the very high titer or 10 IU/mL) had a repeat IGRA 1-6 months later and 8 were negative!!
  • This article cites several studies and systematic reviews finding higher rats of reversions (to normal) and conversions (to positive) than TSTs.

Primary Care Corner with Geoffrey Modest MD: Menopause Symptom Treatment

14 Mar, 16 | by EBM

By Dr. Geoffrey Modest

There was an intriguing editorial written by JoAnn Manson and Andrew Kaunitz suggesting that the pendulum has swung too far, and that too few women are receiving hormone therapy for menopausal symptoms (see N Engl J Med 2016: 374; 803).

Their points:

  • We are an aging population: by 2020 there will be >50 million US women >51 yo (mean age of menopause)
  • 75% have symptoms of menopause; women with moderate-to-severe symptoms often have them for more than 10 years. Symptoms include poor sleep, mood changes, difficulty concentrating and impairment of short-term memory.
  • The most effective therapy for moderate-to-severe symptoms is hormone therapy.
  • Overall, about 20% of women have such severe symptoms, have no contraindication to hormone therapy (e.g. excessive risk of breast cancer/cardiovascular disease; and I would add thrombotic events, active liver disease, stroke, and, to be safe, any thrombophilic disorder), and most remain undertreated
  • Background here: in the past huge numbers of women received hormone replacement therapy in an attempt to decrease cardiovascular events/mortality and preserve bone strength, until the Women’s Health Initiative found increased cardiovascular mortality in its initial report in 2002. This lead to an 80% decrease in hormone prescribing [I would add that at that time we were also getting better, well-tolerated meds for these issues: statins and bisphosphonates, which seemed a much more reasonable and well-studied approach]
  • But the WHI looked at long-term therapy in older women (mean age 63), and may have little relevance to women in their 40s-50s on shorter courses of therapy for these distressing and sometimes functionally-impairing symptoms
  • One consequence of our not treating menopausal symptoms well is the proliferation of non-regulated compounded hormone products (a recent survey found that 35% of current hormone users are on these products)
  • But hormone therapy is really well-studied, with:
    • Much lower risk of adverse events in those in their 50s vs older, including, in events per 1000 women over 5 years (the data is significantly better for those on conjugated equine estrogens CEE alone vs with medroxyprogesterone MPA):
    • Death from any cause: -5.5 (i.e. benefit) in those on CEE vs -5.0 on CEE/MPA
    • ​Fractures: -8.0 with CEE vs -12.0 for CEE/MPA [though actually hip fractures may be worse with CEE but better with CEE/MPA]
    • All cancers: -4.0 with CEE vs -0.5 for CEE/MPA
    • Diabetes: -13.0 with CEE vs -5.5 for CEE/MPA​
    • Coronary heart disease: -5.5 with CEE vs +5 for CEE/MPA
    • Deep venous thrombosis: +5 with CEE vs +5.0 for CEE/MPA
    • Breast cancer: -2.5 with CEE vs +0 for CEE/MPA [the decreased risk of breast cancer in those on just CEE was found in the Women’ Health Initiative]
  • The data are reasonably robust that transdermal estrogens are even safer [bypass the first-pass hepatic metabolism of oral meds, with documented decreases in vitamin K-dependent clotting factor induction, and observational data of many fewer DVTs; also oral estrogens more associated with high triglycerides and CRP levels]
  • Also undertreated is vulvovaginal atrophy, occurs in 45% of women, adversely affects physical and sexual health/quality of life, and responds well to topical vaginal estrogens
  • And there is a concern that new physicians are not receiving training in prescribing hormones, as verified in studies showing that 3/4 of internal medicine residents understand the importance of treating menopausal symptoms, yet 3/4 felt they did not get adequate training

A few comments:

  • Although I do prescribe medications for disconcerting menopausal symptoms, I usually will suggest to the patient trying nonhormonal meds first (e.g. SSRIs, SNRIs, clonidine, gabapentin, the data on herbal medicines is pretty mixed, as are the data for exercise. Weight loss can help. I have prescribed mostly venlafaxine but it seems that pretty much all SSRIs and SNRIs work). But the vast majority with severe symptoms do require estrogens. Almost always, I suggest transdermal estrogens, for reasons noted above, and typically have had great success with that.
  • Women with intact uteri should have a progestin prescribed, since endometrial hyperplasia can happen within months of starting estrogens. Though not great data for this, I tend to prescribe micronized progesterone (as opposed to MPA, micronized progesterone does not decrease HDL levels). Aome people do well with progesterone-secreting IUDs, though there is some (probably minimal concern) that increased blood levels of progesterone can occur and one observational study did find a higher breast cancer incidence. I have not prescribed this so far, but it sounds pretty good to me…
  • Also, my experience is that most women spontaneously stop the therapy within a couple of years, though some have recurrent symptoms (tapering the dose sometimes works)
  • So, the risk of hormone therapy is really very low in young, healthy women taking these meds for 5 years. I share the editorialists concerns that we are probably undertreating a condition which really affects women’s lives/functioning, and that we are not adequately training residents/new physicians in feeling comfortable with well-researched therapies.

For more detail on menopause treatment studies and other recommendations, see practice guidelines by the Endocrine Society:  J Clin Endocrinol Metab 100: 3975)

See blog http://blogs.bmj.com/ebm/2015/02/21/primary-care-corner-with-geoffrey-modest-md-length-of-menopausal-symptoms/​ which noted that 20% of women have menopausal vasomotor symptoms 13 years post-menopause, much longer than noted in many published guidelines.

Primary Care Corner with Geoffrey Modest MD: Profits From Cancer Drugs – Further Drug Company Shenanigans

11 Mar, 16 | by EBM

By Dr. Geoffrey Modest

BMJ just had another of their many articles on drug company malfeasance, this one on mega-profits from their packaging of cancer drugs​​ (see BMJ2016;352:i788). The authors are from Memorial Sloan Kettering in New York and the University of Chicago.

Details:

  • Background:
    • The issue is that cancer drugs dosed by body size are often in single-dose vials and are typically packaged in quantities larger than needed.
    • The leftover drug, which could have been used for another patient, needs to be used within 6 hours and only in specialized pharmacies.
    • Hospitals and doctors also profit by buying these meds through the “buy and bill” system (they buy the drugs, then bill the insurers but with a mark-up which can vary widely — the current Medicare mark-up is 4% but can be as high as 58% if the hospital has a 340B pharmacy (see below), for commercial insurers it is 22% for doctors and 142% for hospitals and even higher through a 340B pharmacy). And they benefit more from buying more drug than they use.
  • Extent of the problem:
    • The researchers looked at the top 20 cancer drugs that are dosed by body size and packaged as single-dose vials (which they say accounts for 93% of all sales of such drugs)
    • Their methodology: estimate how often vial-sharing occurred (using Medicare claims, from which they can ascertain the amount of drug used that did not total the full vial contents); then calculate what they thought would be the most efficient packaging method based on the general US population height/weight measurements from the National Health and Nutrition Examination Survey, which they adjusted “to mirror a cancer patient population”
    • Their estimate: 10% of the drugs are discarded. But this seemingly small % translates to $1.8 billion from the $18 billion in sales. the amount discarded varies by drug (from 1-33%), for example:
      • Rituximab: 7% of $3.9 billion was discarded, for a loss of $254 million (and drug company profit of the same)
      • Carfilzomib: 33% of $697 million was discarded, for a pretty similar loss of $231 million
    • Sensitivity analyses did not provide much variation:
      • If the drugs were prescribed at the highest dose suggested by the FDA, the overall loss would be $1.4 billion
      • If every cancer patient weighed 10% lower than the survey population, the loss would be $2 billion
    • Why are there such variations in waste?
      • It really varies by drug packaging, e.g.:
        • Bendamustine (used for leukemia) is packaged in varying sized vials (25, 45, 100, and 180mg), so there can be pretty precise dosing/minimal waste
        • Bortezomib (used to treat multiple myeloma) only comes in one size (3.5 mg vial), which is much larger than the average dose of 2.5 mg, with $309 million in waste (in the UK the drug is sold in 1mg vials)
        • ​Pembrolizumab was initially marketed as 50-mg vials, then was changed so that 100-mg vials were the only ones made in the US (vs continuing the 50-mg vials in Europe). The average 70 kg patient needs 140mg of drug (ie three 50-mg vials, with minimal waste, or two 100-mg vials with lots of waste). So, the net effect of the repackaging is an extra $1.2 billion for the company over the next 5 years.
      • Hospital and doctor billing, and the effects on patients
        • As above, there are considerable markups by hospitals and doctors, which is projected to translate to > $1 billion in 2016
        • In terms of patient costs, about 1/2 of cancer patients have Medicare B, which has 20% copay and no upper limit, and 14% of them have no additional coverage for their coinsurance.
      • Other diseases:
        • Infliximab (one of largest selling drugs in the US at $4.3 billion in 2015, used for a variety of inflammatory conditions) is only available as 100mg single dose vials, which by above type of calculations leads to $500 million in extra revenues for the drug company.
        • ​Omalizumab (for asthma), used in 75 mg dosing increments, is available only as 150 mg vials
      • Conflicting regulations
        • One issue is conflicting regulations: e.g.
          • FDA: encourage drug companies to package drugs responsibly to minimize waste
          • Medicare: okay to share open vials with other patients, if precautions taken
          • But, CDC: only use single dose vials for one patient.

So, a few points:

  • Yet again we are confronted with drug companies making huge profits by manipulating the system. The Feds deserve some credit/blame for not having a consistent directive on using leftovers of these extremely expensive drugs, as I do all the time with leftover lidocaine or immunizations from multi-use bottles (there may be issues of shelf-life that vary with different drugs, of course). But the bigger regulatory let-down is that, unlike almost all other countries, we have no regulatory restraints on the drug industry. They can charge whatever they want. As we see again and again. For example, when the new drug for hepatitis C infection Harvoni came out, there was not even the pretense that the price reflected drug company reported costs (however inflated they might be), but instead were considered “reasonable” given the cost of treating the complications of otherwise untreated hep C.
  • The 340B program began in 1992 to “stretch scarce federal resources as far as possible, reaching more eligible patients and providing more comprehensive services.” The goal of the 340B pharmacy act was to make meds more available at a lower price in areas of need, not to allow larger profits for hospitals and doctors.
  • The magnitude of these profits is shocking/mind-numbing (and, remember, the $2 billion/yr is only for the top 20 cancer drugs). Just think how many more uninsured/underinsured people in the US could receive accessible, affordable care if the $$ were channeled there instead of drug company coffers…..

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