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Archive for August, 2013

Primary Care Corner with Geoffrey Modest: New Guidance re Occupational HIV exposure

28 Aug, 13 | by EBM

the US public health service just published new guidelines for healthcare workers with potential HIV exposures ( see hiv occup exposure guidelines 2013 DOI: 10.1086/672271, or  http://www.jstor.org/stable/10.1086/672271 ). these are a pretty profound deviation from the previous guidelines, as follows (and, of course, these guidelines reinforce the importance of minimizing exposures as the primary approach):

–these guidelines are mostly based on the fact that there are newer and earlier tests for HIV (with the new 4th generation assays, which include the p24 antigen and antibodies to both HIV-1 and HIV-2), and that there are easier-to-take and more tolerable prophyllactic (ie, treatment, since there are no new significant data on prophyllaxis) regimens.

–so, even though HIV transmission is low (0.3% for percutaneous, 0.09% mucous membrane exposure), the working group suggests post-exposure prophyllaxis whenever there is an occup exposure (blood or other possibly infectious fluids), with 3 drugs started ASAP after exposure and given for 4 weeks. preferred regimen of truvada (tenofivir and emtricitabine) plus raltegravir. should try to get HIV (and, i would add, hep b and c) status of the source patient. if known, should modify this regimen depending on the HIV resistance pattern if the source patient has HIV. the exposed worker should have close followup, with initial followup appointment within 72 hours.  so, these guidelines are remarkably easier than the 2005 ones, which required subjective assessment of the quality of the exposure as the guide to prophyllaxis with either 2 or 3 drugs.

–one issue is that ralteg is bid.  there is a new once-a-day integrase inhibitor (dolutegravir) which is once daily and seems very very very promising (see hiv dolutegravir vs raltergravir lancet 2013 http://dx.doi.org/10.1016/S0140-6736(12)61853-4, for example), but i don’t think it is available yet.  there are a slew of other potential regimens besides truvada/ralteg, if you are concerned about other toxicities, including (for example), either darunavir/riton, rilpivirine, atazanavir/ritonivir, lopinavir/riton, along with tenof/emtric (truvada) or AZT/3TC.  all listed in their table A1, with dosing/toxicities in their table B1.

–remember to check on drug-drug interactions with meds the worker is taking.  there is a section in the guidelines addressing if the worker is pregnant/breast-feeding

–since the new assay is more sensitive and picks up infection sooner, can decrease the followup testing to 4 months (vs 6 months)

needless to say/write, these guidelines do not incorporate other potentially transmissible bugs (eg hep b and c).

for specific clinical help if needed, you can contact the following (in the US)(i have used the HIV warmline many times to get input on clinical management of cases, and it is really great):

    HIV warmline (general HIV cases) — 800-933-3413

    HIV PEPline (postexposure prophyllaxis) — 888-448-4911

    HIV Perinatal HIV hotline — 888-448-8765

geoff

Primary care corner with Geoffrey Modest: finasteride doesnt worsen prostate CA survival

27 Aug, 13 | by EBM

recent publication looked at the longterm effects of finasteride (see N Engl J Med 2013;369:603-10, DOI: 10.1056/NEJMoa1215932).  the 15-year survival rates were no different between groups (78.0% with finasteride and 78.2% with placebo).  the 10-yr survival rates for men with low-grade prostate cancer was 83% with finasteride and 80.9% with placebo; for high-grade prostate cancer: 73.0% vs 73.6%

so, pretty clear that not so useful to try to prevent prostate cancer with finasteride (to me, would have been surprising to be beneficial, since the high grade tumors are more dysplastic and less likely to respond to normal endocrine stimulation which is blocked by finasteride). but, at least this study shows that finasteride is pretty benign (i have been hesitant to use it for BPH because of the initial findings, but will use more now if indicated clinically).   

geoff

Primary Care Corner with Geoffrey Modest: Exercise for better memory?

8 Aug, 13 | by EBM

piece in new york times today (see http://well.blogs.nytimes.com/2013/08/07/how-exercise-can-help-us-learn/?hpw) which suggests that studying while doing low-level exercise improves memory.  there was also an article in one of malcolm gladwell’s books finding that, in a crossover study, kids that exercised before an exam had a dramatic improvement in their scores, as compared to no exercise. unfortunately, the trend in society is to cut out exercise as part of the school curriculum, and it continues to be very difficult for many of us (including my patients) to fit exercise into our over-determined/overcommitted daily schedules.  geoff

Primary Care Corner with Geoffrey Modest: New COPD guidelines more patient-centred

8 Aug, 13 | by EBM

the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has just come out with new guidelines (to see document summary, go to http://www.guideline.gov/content.aspx?id=43794.  The AHRQ (agency for healthcare research and quality) just promoted the new guidelines and provided a brief synthesis of the document. will also add the useful out-patient management reference (see http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf). in brief:

–COPD, a common and preventable/treatable disease, which is progressive and assoc with significant personal as well as social/economic consequences

–should be considered in anyone with dyspnea, chronic cough or sputum production and history of exposure to risk factors (cigarette smoke or other noxious particles such as smoke from biomass fuels — occup and environmental exposure)

–spirometry required to make dx, with post-bronchodilator FEV1.0/FVC <0.70, which is similar to recommendations by ACP/ACCP/ATS/ERS (am college physicians, am college of chest physicians, am thoracic society and european resp society)

–important to assess severity of disease including functional effects on patient (impact on health status, activities, etc), social supports, and risk of future events (exacerbations, admissions, death); also need to assess common comorbidities (cardiovasc, skeletal muscle dysfunction, metabolic synd, osteoporosis, depression, lung cancer) in overall assessment of specific patient.  important to know particulars of patient’s dz (timing/precipitants of exacerbations). and, ability to reduce exposures (smoking, environ/occup exposures). one validated tool to assess symptoms is the Modified British Medical Research Council (mMRC) questionnaire (see http://copd.about.com/od/copdbasics/a/MMRCdyspneascale.htm). GOLD also reinforces some older studies (there was one in the annals of internal medicine around 20 years ago) which find (not surprisingly) that, controlling for pack-yrs of cigarettes, people with COPD have higher risk of lung cancer (3-times higher in the annals study). unlike the ACP/ACCP/ATS/ER recommendations, GOLD does suggest that the following studies “be considered”: CXR, CT, diffusing capacity, a-1 antitrypsin, exercise testing — not so much to diagnose COPD but may be important in overall assessment of patient/significant comorbidities/treatment

–treatment: meds do not alter long-term decline of lung function (though: smoking cessation and removal of noxious exposures does help!!), but are important to decrease symptoms/reduce exacerbations. flu/pneumococcal vaccines important . meds: inhaled bronchodilators prn, they do note that “choice of b-agonists, anticholinergics, theophylline or combo therapy depends on individual patient’s response”. they comment on potential cardiac events with anticholinergics, but suggest that further studies are needed. inhaled steroids help (though no comment that the actual studies are really all over the map here: some with good response to steroids, some with none. i personally do try steroids early on in therapy, but stop them if no clinical benefit, since data do not suggest that steroids actually alter the natural history of COPD). moderate-to-severe COPD (FEV1.0<80% of predicted) may respond better to combo long-acting b-agonist (LABA) plus steroid, vs individual component. recent meta-anal showed decreased mortality with combo. some increased risk of pneumonia, though. some (meager) data that triple combo (LABA/steroid/tiotropium) is better (and i have many patients on this combo with apparent clinical improvement over double therapy). some likely further improvement with 15-20% dec in severe exacerbations in pts with poorly controlled chronic bronchitis by adding roflumilast to steroids, though i’m not aware of any data on the incremental effect of adding roflumilast to full triple therapy as above.they do not suggest routinely using antibiotics (eg azithro), mucolytics, antitussives (though i do occasionally use codeine-containing antitussive in patients who are unable to sleep because of cough), vasodilators.

–the GOLD management reference (see above)divides patients into 4 categories (analogous to asthma guidelines), with proposed treaments:

A= low risk less symptoms (<2 exacerb/yr, low mMRC of <2) — short acting b-agonist or anticholingeric   —  mMRC of 1 is “I only get breathless with strenuous exercise”.

 B= low risk more symptoms (<2 exacerb/yr, but mMRC>=2) — LABA or LA anticholinergic — mMRC of 2 is “On level ground, I walk slower than people of the same age because of breathlessness, or have to stop for breath when walking at my own pace”

— C= high risk less sx (>=2 exacerb/yr with mMRC<2 — inhaled steroid plus LABA or LA anticholinergic

— D= high risk more sx (>=2 exacerb/yr with mMRC>=2) — inhaled steroid plus LABA and/or LA anticholinergic

GOLD more assertive in using combo therapies than previous guidelines

–pulm rehab (which we undoubtedly underuse in primary care). consider pulm rehab in anyone “who gets short of breath when walking on their own pace on level ground”.  improves exercise capacity, dec pt perception of breathlessness, improves health-related QoL, dec hospitalizations,dec anxiety/depression assoc with COPD, improves survival and recovery after hospitalization, improves response to LABAs. benefits extend beyond the immediate period of rehab. Note that this is a much more inclusive guideline than ACP/ACCP/ATS/ERS, which really pushes pulm rehab for symptomatic patients with FEV1.0<50%

–oxygen therapy (>15 hrs/d) in pts with severe resting hypoxemia (PaO2 <55mmHg or SaO2 <=88% with or without hypercapnea and confirmed twice over a 3 week period. unlike ACP/ACCP/ATS/ER, GOLD suggests oxygen therapy if PaO2=55-60 or SaO2 of 88% with evidence of pulmonary htn, periph edem or hct>55%

–recommendations for surgery (lung volume reduction, bullectomy, transplant) in selected patients (see paper for details)

–palliative care, end-of-life-care, hospice — should be discussed with patients given predicted pulmonary decline (again, undoubtedly not done enough by us guys)

–for acute exacerbations, antibiotics if evidence of: increased sputum purulence, increased sputum volume and increased dyspnea, esp in moderately to severely ill pts; or if 2 of these symptoms with one being increased sputum purulence, or anyone on mechanical ventillation.  for 5-10 days.

the biggest difference (to me) with previous guidelines is attention paid to patient-centered care — ie, we should not be treating FEV1.0’s (esp since they do not correlate so well with clinical disease), but look at the individual’s symptoms,  and risk of exacerbations.

i would add: i think it is really useful to know the specific clinical course of the individual patient, what their precipitants are to exacerbations, how bad are the exacerbations and historically what works for them.  early treatment is effective in preventing admissions/intubations. so, i have some patients with COPD who get more aggressive baseline treatment during the winter, if URIs are their usual precipitant. some patients with very severe COPD/many hospital admissions even get prednisone at home to take when they are beginning to get an exacerbation (i go through the indications for starting prednisone in detail with them) — and this has undoubtedly decreased admissions/intubations for some of them.

geoff

Primary Care Corner with Geoffrey Modest: Perioperative beta blocker Gdlns outdated…

5 Aug, 13 | by EBM

BMH open access with impressive meta-analysis on the use of perioperative b-blockade to prevent deaths in non-cardiac surgery(see  http://dx.doi.org/10.1136/heartjnl-2013-304262). the issue here is that much of the push for b-blockade came from profound mortality benefit found in the DECREASE family of trials (6 dutch trials, which have largely been conclusively discredited because of “fictitious methods”, “factitious adjudication committee”, and in one case “the entire study dataset had been fabricated”).  even though these trials were exposed and discredited 2 years ago, the European Society of Cardiology and American Heart Association guidelines  still endorse periop b-blockade; 2009 recs for AHA is to initiate perioperative b-blockage with dose titration in pts undergoing vascular and ischemia on pre-op testing, vascular surgery and established  CAD, vascular surgery and more than one risk factor, and intermediate-risk surgery and CAD or more than one risk factor.  the meta-analysis:

–11 RCTs met eligibility criteria, using bisoprolol, metoprolol, atenolol and propranolol. some diff on when ititiated b-blockers — from 37 days to 30 min prior to surgery and continued 5 to 30 days after.

–10,529 pts in 9 trials assessed all-cause mortality and found 162 deaths in 5264 pts on b-blockers and 129 in 5265 pts on placebo (increased mortality of 27%), with little heterogeneity between trials

–6 RCTs assessed MI — 27% decrease in non-fatal MI with b-blockade, BUT 73% increase in stroke and 51% increase in hypotension. (i sent out the POISE trial a couple of years ago: see orDOI:10.1016/S0140-6736(08)60601-7, which was by far the largest, well-done trial of the group, finding dramatic increase in strokes)

–so, by the authors calculation: refraining from the european cardiol guidelines would likely prevent up to 10K iatrogenic deaths/yr in the UK)

so, though we don’t have all the data we would like (eg, the studies included wide range of surgeries, such as abd, ortho, urolog, gynecolog, plastic — so not  sure if benefit might be different with different surgeries), we are likely traversing the “do no harm” boundary. the issue for us guys is that the guidelines, though old and predating the rather striking exposure of the DECREASE trials, are still standing and it is often hard for primary care or surgeons to buck them.  for example, i had a patient a couple of years ago, for whom the surgeon insisted on b-blockers even though i sent him the POISE study, so i had to do it to have the surgery done… ie, we need updated guidelines.

also, when looking at outcomes, all are not equal.  i, personally, would prefer a nonfatal MI to a stroke.

geoff

Primary Care Corner with Geoffrey Modest: Statins and Macrolides

2 Aug, 13 | by EBM

a few articles have come out on statins recently. one in the annals of internal medicine assessed toxicity in patients on macrolide antibiotics. the issue here is that 3 statins (atorvastatin, simvastatin, lovastatin) are metabolized by cytochrome P450 isoenzyme 3A4 (CYP3A4), as are clarithromycin and erythromycin (but not azithromycin). studies in healthy volunteers show that taking clarithro or erythro lead to 10-fold serum increases in simvastatin and lovastatin levels and 4-fold increase in atorvastatin. in this setting, and since statin toxicity is greatest in older individuals, a large population-based cohort study was done in Ontario, looking at all people >65yo on statins and prescribed erythro (done minimally), clarithro and azithro (see doi:10.7326/0003-4819-158-12-201306180-00004).  results:

–75K people on combo of statin and clarithro or erythro, 65K on azithro between 2003-2010

–clarithro/erythro assoc with

–2-fold increased risk of hospitalization with rhabdomyolysis (though only an absolute increased risk of 0.02%) — as a reference here, baseline risk of rhabdo for all ages is 0.5-1/10K person-yrs, though higher in older people

–78% increase in acute kidney injury (1.3% absolute increase risk)

–56% increased all-cause mortality (0.25% absolute increase)

so, this suggests a few things:

-either avoid clarithro/erythro in those on these statins, or hold the statin therapy during short course of these antibiotics. consider using azithro as alternative (my guess is that one of the more common usages of clarithro now is in treating h. pylori infections. clarithro has been tested in many studies on hpylori treatment. there are some intriguing but limited data on azithro, including the fact that azithro 500mg on an empty stomach maintains tissue levels of the antibiotic for many days, with one study finding a 3-day course of PPI plus tinidazole 1000-2000mg, and azithro 500 had a 85% cure rate (other data are less impressive, though may be related to azithro being taken with food, which decreases its blood levels). at this point, i would still stay with clarithro, given the abundance of studies.

-the CYP3A4 issue also applies to other drugs, including several of the HIV meds, which affects which statin to use (and given that HIV is now more of a chronic disease with long life-expectancy though a higher risk of heart disease, statins are frequently prescribed)

-one confusing issue is that non-CYP3A4 metabolized statins (eg rosuvastatin) still seems to have some drug-drug interactions with the HIV meds. i have a patient with diabetes and essentially every cardiac risk factor known  plus HIV. the preferred statin is pravastatin (though not strong enough for this patient), so i started rosuvastatin after speaking with HIV pharmacologist, but was told to give only 1/2 the dose since ritonivir doubles the rosuvastatin serum level.  i raise this just to show that the whole situation is more complex than just the P-450 metabolism.

geoff

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