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Archive for February, 2014

Primary Care Corner with Geoffrey Modest MD: Selenium and vitamin E may increase risk of prostate cancer

28 Feb, 14 | by EBM

New study in JNCI attempted to sort out diverse findings on prostate cancer development in men supplemented with selenium or vitamin D or both. (see DOI:10.1093/jnci/djt456). Previous data has shown:

–From the selenium and vitamin E cancer prevention trial (SELECT) in 2001, a prospective study of 35,533 men randomized to one of 4 groups (selenium 200 mcg/d plus vitamin E 400 IU/d, vitamin E plus placebo, selenium plus placebo, or just placebo), there was no benefit from these interventions, and a significantly increased risk of prostate cancer by 17% with vitamin E supplementation alone
–The nutritional prevention of cancer trial (NPC), a study of 928 men who lived in an area of the US with low soil selenium levels, found that men with moderate or low selenium levels and given supplementation with selenium had a decrease in prostate cancer risk by 75%.  This was not found in men who had high plasma selenium levels at baseline.

this current study was a cohort study comparing 1739 men with prostate cancer (489 with Gleason 7-10) from the SELECT trial with a randomly selected subcohort of 3117 men, also a from the SELECT trial.  They assessed whether selenium and vitamin E supplementation effect on prostate cancer was conditional on baseline selenium status.  Findings:

–Toenail selenium levels at baseline was not associated with prostate cancer risk
–Supplementation with selenium only or selenium plus vitamin E had no effect on prostate cancer in men with low baseline selenium levels in their toenails, but found a 91%  increased risk of high grade prostate cancer in men with a higher baseline selenium status.
–Vitamin E supplementation alone had no effect among men with high selenium status at baseline, the but had an increased risk of prostate cancer by 63% (total, low-grade, and high-grade) in men with lower selenium baseline status.
–When these investigators assessed the data using the cutpoints of the NPC trial above for baseline selenium concentrations, they could not reproduce any positive effect of supplementation. (though note that the NPC study was much smaller than the SELECT one).
–a couple of caveats to the current study: Toenail selenium concentrations are  not a perfect measure of actual selenium absorption and metabolism, and does not measure the functional activity of selenium-dependent proteins in prostate and other tissues.  Also there were very few black patients involved in the SELECT trial.

So, bottom-line, supplementation with selenium and vitamin E did not help, and in certain groups (e.g. selenium supplementation in those with high baseline selenium levels, and vitamin E supplementation alone in those with low selenium levels) was associated with increased prostate cancer risk.  We do know from many different studies that good nutrition is associated with lower levels of heart disease and cancer.  However, we repeatedly find in the studies that micronutrient supplementation often does not reproduce these results, and in some cases (e.g. beta-carotene and lung cancer in smokers) is harmful.  The issue here, as I pointed out in many prior blogs about micro-nutritional supplementation, is that there is likely an important interplay between the different nutritional components to foods as well as a balance of the amounts of each one, and there is been a long evolutionary history of humans consuming an array of appropriate vegetables, for example, which provide the appropriate mix.  The reductionist approach of trying to isolate specific micronutrients as a magic bullet to prevent disease and then supplementing with a supraphysiologic dose is therefore both conceptually problematic and typically clinically unsuccessful (with the possible exception to vitamin D, which is not largely nutritionally-derived, and deficiency may well create problems in those in untoward northern climates).



Primary Care Corner with Geoffrey Modest MD: Aspirin decreases risk of ovarian cancer

27 Feb, 14 | by EBM

Just after my sending out an article on aspirin in primary prevention of heart and other diseases, JNCI  has conveniently published an assessment of aspirin and ovarian cancer (see doi:10.1093/jnci/djt431). in this study the Ovarian Cancer Association Consortium reviewed the literature, finding 12 population-based case-controlled studies between 1992 and 2007, which included 7776 patients with ovarian cancer and 11,843 control subjects.  Findings:

–Overall ovarian cancer risk was reduced 9% with the use of aspirin
–Non-significant but similar reduction was found for non-aspirin NSAIDs, and no association with acetaminophen use
–7 studies assessed the frequency of aspirin use, finding that risk reduction was strongest among daily aspirin users, with a 20% risk reduction
–3 studies included dose information, finding that low dose aspirin (< 100 mg/d) was associated with the greatest risk reduction (34%). the studies also found that high dose of non-aspirin NSAIDs (>= 500 mg) was associated with a 24% reduced risk, but no relationship with acetaminophen
–Tumors of low malignant potential (n= 2059) were not associated with analgesic use (ie, it was not just the low-grade tumors that were decreased).  Aspirin use was associated with reduced risks of serous, endometrioid, and mucinous ovarian cancers (though only serous cancers reached statistical significance)

 so, ovarian cancer is the most lethal gynecologic malignancy with greater than 140,000 deaths per year worldwide.  There are some data suggesting that ovarian cancer may be related to chronic inflammation, creating a plausible mechanism for aspirin protection.  As I mentioned in a previous blog, there are relatively consistent data on aspirin use and decreased colorectal cancer (risk reduction on the order of 50%), but there also data of reduced risk of cancers of the esophagus, bladder, liver, lung, endometrium, and female breast.  It is important to remember that these are all secondary analyses of studies and therefore prone to bias.  However, these studies and their consistency do sway me to prescribing low-dose aspirin to people who are on the borderline for aspirin use for cardioprotection.


Primary Care Corner with Geoffrey Modest MD: Striking successes with non-interferon, non-ribavirin therapy

26 Feb, 14 | by EBM

the journal Gastroenterology just published a short-term oral (ie non-interferon based) and ribavirin-free regimens for genotype 1 hepatitis c infection. important since ribavirin does have some significant adverse reactions, including anemia.

–phase 2 open-labeled study of 66 treatment-naive patients (see doi:10.1053/j.gastro.2013.10.057) with hep c, genotype 1 and RNA level >100,000, and without cirrhosis (either non-invasive FibroTest being low, or if high then a biopsy negative for cirrhosis), given daclatasvir 60mg/d (an NS5A replication complex inhibitor), asunaprevir 200mg bid (an NS3 protease inhibitor) and BMS-791325, either 75mg or 150 mg bid (a non-nucleoside NS5B inhibitor) for 12 or 24 weeks. (so, about 16 pts in each group: either shorter or longer therapy, and either 75mg or 150mg of the  BMS-791325). primary endpoint of HCV-RNA level <25 IU/ml at 12 weeks after treatment (SVR12). results:

–in 64 patients HCV-RNA suppressed by week 4 of treatment. (includes 48 of 49 with genotype 1a infection, and 45 of 46 with non-CC interleukin 28B genotype — these are less responsive to interferon)
–61 pts (92%) achieved SVR12.
–no diff if 12 or 24 weeks of therapy; no diff if 75mg or 150mg of BMS-791325; no diff if genotype 1a or 1b.
–no serious adverse events, mostly headache, asthenia, and GI symptoms

so, a whirlwind of new studies have come out in the past couple of years on interferon-free and now ribavirin-free regimens, with striking successes with short-term therapy.  these are really remarkable advances. (though, as with the previous blogs on this subject, they will no-doubt be a tad costly).


Primary Care Corner with Geoffrey Modest MD: Lung auscultation

25 Feb, 14 | by EBM

NEJM just came out with review article on lung auscultation (see doi: 10.1056/NEJMra1302901). it does seem that we are moving towards using echocardiograms instead of cardiac auscultation, bolstered by studies confirming that cardiologists ain’t so great at predicting whether a murmur is from the right or left side of the heart. and, seems that at the slightest hint of lung problems, CTs are the way to go. although i am being a tad sarcastic, my sense is that medical students/residents/perhaps some of the younger attendings are not as fluent as some of us more traditionally-trained ones (a euphemism for older ones….) so, will circulate this article. a few points:

–some of the nomenclature has evolved over the years. for better or worse, rales don’t exist anymore. just crackles. and “moist” vs “dry” is out (turns out that one person’s moist is another’s dry, and neither seemed to correlate with much), though there are fine vs coarse crackles (fine being short, heard mid-to-late inspiration, nonclearing with cough, and associated more with interstitial fibrosis, CHF, pneumonia; coarse being early inspiratory and throughout expiration, clear with cough and often related to secretions). and now there are “squawks”, with a short musical component/short wheeze, accompanied or preceded by crackles (signifying problem with distal airways, could be interstitial lung dz or pneumonia)
–their table is a good (xeroxable) one of the different sounds and where they come from/what they usually mean.
–and, just to show the value of auscultation, in a study of 386 workers exposed to asbestos, auscultation-detected crackles were 100% accurate in identifying asbestosis, i.e. as good as CT (they were obviously looking for it/listening with a focus, but pretty impressive anyway)


Primary Care Corner with Geoffrey Modest MD: Citalopram improves Alzheimer’s agitation

24 Feb, 14 | by EBM

JAMA this week reported on the use of citalopram for agitation in people with Alzheimer’s disease (see doi:10.1001/jama.2014.93). details:

–double-blind study of 186 pts with probable alzheimer’s and agitation (mean age 78, 46% women, 65% white, 70% on cholinesterase inhibitor and 42% on memantine) at 8 US and Canadian academic sites, all with 9 week psychosocial intervention, half with citalopram (began at 10mg, titrated up to 30mg over 3 weeks, and with 78% achieving the 30mg target). psychosocial intervention consisted of giving educational material, 24-hr availability for crisis management, and 20-30 minute counseling session at each visit, focusing on reviewing/adjusting supportive care plan, providing emotional support, counseling regarding specific caregiver skills, and assistance with problem solving on specific caregiver/patient issues.  At 9 weeks:

–18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) with 1 point improvement (felt by editorialist to be clinically significant) with citalopram.
–modified Alzheimer Disease Cooperative Study- Clinical Global Impression of Change (mADCS-CGIC) found 40% on citalopram to have moderate or marked improvement, vs 26% placebo. (OR 2.13)
–those on citalopram also had improved Cohen-Mansfield Agitation Inventory, Neuropsychiatric Inventory, and caregiver distress scores (but, no improvement in Neuropsychiatric Inventory scale, ability to complete ADLs, or in less use of rescue lorazepam,  AND there was worsening of cognition by 1 point on Mini Mental Status Exam (though unclear clinical relevance of this small a change; typically a 1.4 point change is considered significant) and increase in QTc by 18.1msec.

so, a few points of interest.

–neuropsych sx are really common in Alzheimer’s. antipsychotics have been used lots in the past, with unclear efficacy in the studies, and increased mortality (though they certainly seemed to work in some of my patients…) –given the FDA warning about citalopram dosing and increased QTc, lower doses and closer EKG monitoring seems reasonable. i had posted a previous blog confirming that there is a pretty dramatic increase in QTc with citalopram, but it is important to note that the actual clinical effect of this prolongation is NOT clear: the FDA looked at a large VA database and found that the risk of ventricular arrhythmias and mortality were LOWER in depressed patients on greater than 40mg citalopram/day, similar results to those found in patients on sertraline (i have largely shifted to sertraline as my “go-to” antidepressant overall, away from citalopram because of the QTc issue, but still use citalopram if sertraline not tolerated). anecdotally, a geriatric psychiatrist i know has been using sertraline for agitation in people with Alzheimers, with good effect. citalopram in this study was well-tolerated.
–overall, very impressive but short-term study. i would certainly prioritize nonpharmacologic management, but if insufficient, finding a 40% moderate to marked improvement with decreased agitation is very impressive.


Primary Care Corner with Geoffrey Modest MD: Efavirenz and hormonal contraception

23 Feb, 14 | by EBM

recent report suggesting that efavirenz decreases the efficacy of intradermal Jadelle implant (this is the successor to Norplant, with 2 thin, flexible silicone rods, each containing 75 mg of the synthetic progestin levonorgestrel).

here is the abstract (that is all i could find), from PubMed:

Perry SH, Swamy P, Preidis GA, Mwanyumba A, Motsa N, Sarero HN. AIDS. 2014 Jan 2. [Epub ahead of print] Implementing the Jadelle implant for women living with HIV in a resource-limited setting in sub-Saharan Africa: concerns for drug interactions leading to unintended pregnancies.

“An analysis of 570 HIV-infected women in Swaziland using the Jadelle implant showed that age, condom use, which provider placed the implant, and CD4 cell count had no effect on unintentional pregnancy rates. However, antiretroviral regimen at the time of pregnancy correlated with pregnancy outcomes (P <0.001). None of the women on nevirapine or lopinavir/ritonavir-based regimens (n = 208 and 13, respectively) became pregnant, whereas 15 women on efavirenz (n = 121; 12.4%) became pregnant.”

so, this is a double hit for efavirenz. there are reports that HIV regimens with efavirenz lead to lower progestin blood levels on women on combination oral contraceptives (and recommendations that condoms still be used for contraception, as well as prevention of sexually-transmitted diseases).  this report adds significantly to the prior concerns.  in addition, efavirenz is probably the most teratogenic of the HIV antiretrovirals. so, bottom line, prob best not to choose efavirenz-based therapy on women of child-bearing age…


Primary Care Corner with Geoffrey Modest MD: Aspirin use and prostate cancer

21 Feb, 14 | by EBM

I had posted a couple of articles in the lancet suggesting that aspirin protected against incident cancer and cancer mortality, including in those with metastatic disease. New observational study of 6000 men with prostate cancer (localized adeno, rxd with radical prostatectomy or xrt) and followed 70 months found that, irrespective of the prostate ca therapy, those who happened to be taking aspirin had much lower prostate-specific mortality (3% vs 8%), with dec in both disease recurrence and bony mets. The decrease was particularly impressive in those with “high-risk” disease, wtih prostate-specific mortality 4% vs 19%. Although they looked at all anticoag therapies, the effect was primarily seen with aspirin.  See doi: 10.1200/JCO.2011.41.0308.  So, observational study, but adds to the lancet studies, and prior studies that aspirin/nsaids help prevent colon cancer.


Primary Care Corner with Geoffrey Modest MD: Aspirin and cancer

20 Feb, 14 | by EBM

Lancet also had 2 articles on aspirin and cancer (both from same group in UK).  This is the same impressive group that did a whole lancet issue a few years ago on blood pressure variability and stroke (in a previous post on hypertension).
1. looked at 5 trials using aspirin, at least 75mg/d, to decrease vasc events, with 6.5 yrs followup.  Many old studies suggested dec in colon ca with asa or nsaids, most with positive results. This study of 17K pts found 36% dec risk of distant mets overall in pts with cancer, with the vast majority of effect in adenoca — 48% dec risk of metastases in those with adenoca. Esp effective in those without mets at diagnosis (50% decrease). Essentially all of the graphs show continuing divergence of curves for the first approx 8 years, then plateauing, for lung, bone, brain, and other mets.  The total number of cancers detected and elligible for analysis was 775. (they do not give absolute risk reductions, but to my simplistic analysis, about 5% of pts had cancer, about 50% reduction, so on the order of 2.5% of population with benefit).
Those on lower dose aspirin did the best.  For the most common adenocarcinomas (esp those without mets already), the results were consistent (colorectal 73% reduction, breast 84% reduction, prostate 66% reduction). Pretty impressive. See doi: 10.1016/S0140-6736(12)60209-8
2. study on cancer incidence in pts taking daily aspirin, short-term effects. In 34 trials of 69K pts, 15% dec cancer deaths, esp after 5 yrs. In primary prevention trials of low dose asa (6 trials, 36K pts), after 3 years cancer incidence dec 24%. Initially the benefit of asa was offset by inc bleeding, but that outcome diminished after 3 years, with continuing benefit in cancer incidence. For some reason (??) case-fatality rate from major extracranial bleeds lower on asa, though there was twice the risk of extracranial bleeds in the 1st 3 yrs, no increased risk afterwards.(intracranial bleeds included in “major vascular events” category). Curves on cancer incidence ess the same for first 4 years, then diverge and stay diverged, demonstrating consistent benefit from aspirin. Subgroup analyses (men/women, age more or less than 60, smoker) all show the same, with no real effect for 1st 3 years, but after 3 years there is a consistent absolute reduction of 3 cancers/1000-patient years.  See doi: 10.1016/S0140-6736(11)61720-0. 

Primary Care Corner with Geoffrey Modest MD: Aspirin in primary prevention of heart disease

19 Feb, 14 | by EBM

a recent article reviewed the data on the use of aspirin in  primary prevention, both cardioprotective and chemoprotective (see doi:10.1093/eurheartj/eht058). basically, no new data challenging the old recommendations for primary and secondary prevention of vascular disease: for secondary prevention there is a 20% decreased risk of vascular complications, translating to an absolute reduction of 10-20/1000 pts in annual incidence of nonfatal events (smaller but important reduction in vascular deaths), with absolute increase in major extracranial bleeding complications which is 20-50 fold smaller.  the data on primary prevention is not so impressive. studies difficult to meta-analyze, since different populations and different endpoints. but overall, data insufficient to advocate either for or against aspirin use. there are some data that in certain conditions (eg following CABG, pts with essential thrombocytemia, pts with coronary artery disease who have metabolic syndrome and pts with diabetes), there may be increased platelet activation and may have suboptimal response from aspirin (the POPADAD study was quite striking: men and women with diabetes and peripheral artery disease, at very high risk of other atherosclerotic events, randomized to aspirin 100mg/d vs placebo and no benefit to asprin). the liberal use of statins may provide much of the benefit of aspirin with less toxicity.

a few comments about using aspirin:

1. avoid using enteric-coated aspirin formulations: on the one hand, there is less bioavailability of the enteric-coated and the vast majority of secondary prevention trials used plain aspirin, and on the other hand, it seems that enteric-coated is not gastroprotective (ie, a study found that the relative risks of upper GI bleeding for plain vs enteric-coated vs buffered aspirin (<325 mg) was 2.6, 2.7 and 3.1. if >325 mg, RR was 5.8 for plain and 7.0 for buffered aspirin (not enough data on enteric-coated)

2. risk of bleeding: for extracranial bleeds the risk increases along with all of the major cardiac risk factors, except lipids (ie, increased risk of bleeding if diabetes, male gender, cigarette smoker, hypertension, high BMI).  so, the more likely to benefit from cardioprotection, the more likely to bleed. increased bleeding up to 100-fold, depending also on prior history of GI bleeding and age of patient. GI bleed risk is halved by either adding a proton pump inhibitor or treating underlying H. Pylori infection. (there have been a couple of studies showing, for example, that in H pylori positive patients about to begin chronic NSAIDs for rheumatologic diseases, that pretreating the H pylori dramatically decreases GI bleeding, including severe bleeds). in terms of intracranial hemorrhage, less data, but seems to be <1 per 1000 pts per year in high risk trials. meta-anal of primary prevention trials: 5 additional hemorrhagic strokes per 1000 mod risk pts over 5 years, and much less if low-risk patient.

3. cancer risk: trials for vascular protection have pretty consistently found deceased cancer risk with aspirin (after 8-10 years of low-dose aspirin), and decreased incidence and mortality from common cancers. most consistent data for colon cancer, though all of these are secondary analyses and hard to make real recommendations. will send out again a couple of older email/blogs about use of aspirin in breast cancer, etc.  but, unlike the diminishing vascular protective effect of aspirin after the initial 3 years, the risk of cancer decreases with time (OR of 1 in 1-3 years, improving to 0.81 for 3-5 years and further to 0.70 after 5 years)  and the risk of extracranial bleeds also decreases (increases almost 2-fold for 0-3 years, then not significantly increased).  BUT, if person has been on aspirin for secondary prevention and if they are taken off after 3 years, 40% increased risk of ischemic stroke and MI (ie, DO NOT stop the aspirin because the protection is less evident after 3 years!!)

so, no change in recommendations, but i would advise against enteric-coated aspirin. i also have been incorporating the possible cancer benefit if a patient is on the borderline of treating with aspirin  (eg, by the old framingham risk score, if the risk is in the 6-10% range)


Primary Care Corner with Geoffrey Modest MD: Severe asthma treatment

18 Feb, 14 | by EBM

new guidelines (they just keep comin’…), this time on defn, eval and treatment of severe asthma (see doi: 10.1183/09031936.002020), put out by combo of European respiratory society and american thoracic society. main points:

definition: severe asthma (approx 5-10% of asthmatics) = asthma requiring high dose inhaled steroids (ICS) plus second controller (eg ICS plus long-acting b-agaonist (LABA) or leukotriene modifier/theophylline) for the past year and/or systemic steroids (>50% of the time in the past year) to control, or remains uncontrolled despite this therapy (uncontrolled = poor symptom control, or >=2 bursts of systemic steroids in past yr, or at least one hospitalization in past yr, or FEV1<80% after appropriate bronchodilator withhold.  only after confirm asthma dx — see evaluation section

[there is an extensive section on phenotyping asthmatic kids and adults, which seems to reflect age of onset, gender, severity, proneness to exacerbation, and presents some data on differentiating different phenotypes (eg, whether there is an inflam response, and if so, presence of eosinophils or neutrophils), and some info on different genetics (eg IL4 or IL6 pathways and receptors)/epigenetics.   pretty interesting stuff, which reinforces that asthma is a myriad of different conditions lumped together, and that this knowledge may ultimately determine different treatment approaches.  but, will leave this for you to pursue in the document, if interested]


1. make sure it is asthma (misdiagnosis as uncontrolled asthma found in 12-30%). evaluate sx, triggers, environmental/occup factors. one of common misdiagnoses is respiratory sx related to obesity. they have a table (Table 6) of diseases that can masquerade as asthma in kids (eg, vocal cord dysfunction, bronchiolitis, reflux/microaspiration, foreign body, etc), and in adults (vocal cord dysfunction, copd, panic attacks, chf, etc). pfts with and without bronchodilators (esp after withholding b-agonists) needed for diagnosis. they do recommend that a high resolution chest CT be done in kids and adults with severe asthma and atypical asthma presentation, eg rapid decline in lung function, lots of mucous, etc (low quality evidence).
2. assess comorbidities: nonadherence to rx is most common (32-56%) as cause of “severe asthma”, but comorbidities can make asthma worse (eg, rhinosinusitis, nasal polyps, obesity, smoking, OSA, aspirin, anxiety/depression, etc). GERD is included in list, though role is probably over-rated and anti-reflux rx not help so much.
3. there are some broad phenotypic aspects that can help. for example, those with early-onset allergic phenotype (may respond to anti-IL5 or anti-IL13 therapies), later onset obese phenotype (responds to weight loss more than obese, early onset asthma), late onset eosinophilic phenotype. they have a table (Table 9) with specifically targeted, mostly monoclonal antibody therapies for different phenotypes)


1. there is often a relative ICS insensitivity, such that oral steroids are needed regularly (or IM triamcinolone), though there is less asthma responsiveness in those with obesity, smoking, low vitamin D levels, and non-eosinophilic (esp, it seems, in those with neutrophilic) asthma. there are some novel drugs in the wings for those with corticosteroid insensitivity
2. there are some people who do respond to high-dose ICS (eg fluticasone 500 mcg in kids, or >500 mcg in adults — their table 4 has the list), though in pts with moderate asthma, increasing to these doses is not effective
3. adding LABA to ICS is helpful, and is often more helpful than increasing ICS in patients with moderate asthma (those with severe asthma should already be on high dose ICS). I have posted prior studies showing that African-Americans in general are more likely to be resistant to the effects of b-agonists (short or long-acting), perhaps related to b-adrenoreceptor genotypes. anticholinergics (eg, ipratropium, tiotropium), though usually less helpful than b-agonists, may be very useful in people resistant to b-agonists, and can be added to ICS and LABA.
4. low dose theophylline can help (this sort of fell off the charts several years ago, was revived some with the COPD/GOLD guidelines, and I have found that it helps some people a lot, both with asthma and COPD)
5. they recommend treatment guided by clinical symptoms, though recommend sputum eosinophil counts done in experienced centers is helpful in adults (low quality evidence) but not in kids. they recommend against using FeNO (exhaled nitric oxide fraction) measurements. consider omalizumab in adults and kids (low qual evidence) if severe allergic (IgE-dependent) asthma, if not controlled on regular meds.  not use methotrexate, macrolide antibiotics (in spite of recent study in NEJM on azithromycin). only use antifungals if documented allergic bronchopulmonary aspergillosis (low quality evidence). bronchial thermoplasty may be useful (low quality evidence) in specialized sites. no suggestions about cromoglycates (cromolyn).

so, adds a little to the current approach. highlights importance of accurate diagnosis, including PFTs, and the approach to asthmatic phenotypes, which reinforces the conception of asthma as a variety of unrelated diseases with common clinical presentation, is useful and is opening the door to more specific targeted therapies.



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