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Archive for December, 2015

Primary Care Corner with Geoffrey Modest MD: The Drug Co-shenanigans Reach New Heights

26 Dec, 15 | by EBM

By Dr. Geoffrey Modest

A couple of articles came out in the press showing that drug companies seem to have grovelled to a new low.

  1. A STAT News investigation looked​ into required study reporting by major academic centers, finding pretty dramatic deficiencies .


  • In 2004 the New York attorney general filed a lawsuit against GlaxoSmithKline for concealing data finding that Paxil (paroxetine) was associated with increased suicidal thoughts in teens, which led to federal legislation to ensure that studies from drug and medical device makers report results through the NIH website, or face a fine. The context here was that negative trials, or those finding significant adverse effects, might not be published, leading to clinicians using useless and perhaps harmful drugs or devices. These disclosures were to be reported on the website within one year of study completion or termination, or be subject to a fine of $10,000 per day per trial
  • But, it turns out that compliance with these federal requirements is remarkably poor, especially in big academic centers: 4 of the top 10 recipients of medical research from the NIH filed reports late or not at all in >95% of the time, including Stanford, University of Pennsylvania, University of Pittsburgh, and University of California San Diego. (This was actually much worse than for drug companies…)
  • No one has ever paid a fine for late or non-reporting, which translates to a potential collection of $25 billion from drug companies alone in the past 7 years (as a perspective, the total 2014 NIH budget was $30 billion, which was 14% less than the 2006 budget when adjusted for inflation)
  • An example: in 2009 Hoosier Cancer Research Network terminated a study of Avastin early, with 18 patients being treated for metastatic breast cancer. The drug did not work, but there was serious harm, including hypertension, GI toxicity, sensory problems and pain. This was never reported, and debate of its efficacy continued nationwide. Finally in 2011 the FDA revoked its approval of Avastin for breast cancer.
  • STAT identified 9000 trials in that were subject to the disclosure law, focusing on 98 universities, nonprofits and corporations between 2008-2010. They found that academic institutions either were late or did not file 90% of the time and industry did not file 74% of the time (for us in Boston, it was notable that Beth Israel did not file or was late 91% of the time, Dana-Farber 85%, Mass General 84% and the Brigham was best at 81%)
  • The defense by the academic institutions included the time it takes to download the data (which it turns out is not really a lot), that they did not have enough funding, they were waiting for journals to publish their results, or “some experts voiced concerns that the researchers might also face pressure from corporate sponsors to delay reports — whether negative or positive — for commercial reasons”.
  • By the way, is a pretty useful website, which gives anyone, including patients, free access. Just type in the drug in question and it pulls up studies, some done, some recruiting, and even a few with the results logged in….

Also, a recent article in BMJ open (see 10.1136/bmjopen-2015- 009758) assessed all clinical trials submitted to the FDA for approval in 2012, finding that the FDA approved 15 drugs sponsored by 10 large companies, there were 318 relevant trials with 99,599 subjects, a median of 57% of the trials were registered, and 20% reported results on Per drug, a median of 67% were compliant with FDA reporting rules and 51% of subjects were enrolled in non-compliant trials, with wide variation by company.

A prior blog​ looked at the poor DFA oversight of medical devices. And another in 2013 looked at the large number of trials with unpublished results and not reported in See

So, bottom line: this regulatory consumer protection has been largely ignored by drug companies and academic centers, raising the very real possibilities that providers continue to prescribe drugs that are ineffective (except for the bottom line of the drug companies) and potentially harmful. And, for whatever reasons, the NIH is missing out on $25 billion from fines, which one can only assume could be used by the NIH to partially compensate for their underfunding… (see highlighting that over the past decade there has been a 24% decrease in the number of studies funded by the NIH and a 43% increase in those funded by industry).

  1. The NY Times had yet another article on the unbounded greed of drug companies, centering again on Turing pharmaceuticals (see​ ). This is the company highlighted in a prior NY Times article, where Turing acquired the rights for the anti-toxoplasmosis drug pyrimethamine and immediately raised the price from $13.50 a pill to $750 a pill (see )

The current outlandish act was focused on an old drug used for Chagas disease, where the head of Turing wants to take advantage of the federal program encouraging companies to develop drugs for neglected diseases.  This case involves the drug benznidazole, a treatment used in South and Central America  (where Chagas disease is very common) since the 1970s, but was never approved in the US (though the FDA does give it out for free by the CDC “on an experimental basis”). In Latin America, the drug costs $50-$100 for a 2 month course of treatment. Turing’s CEO Martin Shkreli said that if he got FDA approval for the drug, he would have exclusive rights to sell it and “the price would be similar to that of hepatitis C drugs, which cost $60,000 to nearly $100,000 for a course of treatment”.  And, to boot, Shkreli also felt that it was unlikely they would need to do clinical trials to get FDA approval, “just some smaller, quicker studies” and approval should happen within a year. One comment in the NY Times article that I find quite perplexing is that Congress created a program whereby drugs approved for qualifying tropical diseases can get a voucher for an expedited review by the FDA of another drug (???), and that these vouchers (which decrease the review time by 4 months) can then be sold to another drug company, perhaps allowing them to market a blockbuster drug for a common condition such as diabetes or arthritis, and then have an extra 4 months on the market before the patent expires. And these vouchers have been sold for up to $350 million. Another pharmaceutical did this: Knight Therapeutics won FDA approval for the old drug miltefosine to treat leishmaniasis in 2014, never offered the drug for sale in the US, but sold the voucher to Gilead for $125 million.​

So….. pretty awful.  And, of all things, using the name “Turing” for such shenanigans. I suspect that Alan Turing would cringe and roll over in his premature grave. And, as another aside (and not so surprising) Martin Shkreli was arrested today (12/17) for securities fraud (see )

Primary Care Corner with Geoffrey Modest MD: CDC Postpones Their Opiate Guidelines

24 Dec, 15 | by EBM

By Dr. Geoffrey Modest

So, as an addendum to the blog yesterday, it turns out that the CDC is putting off their draft opiate recommendations because of a huge public outcry, with the following comments in STAT news:

“The postponement follows complaints from representatives of other federal agencies and consumer advocacy groups that the CDC guidelines were based on weak evidence and would unfairly restrict some patients from obtaining needed pain relief. The agency was also chastised for using a “secretive” process to formulate the guidelines, which some critics argued had violated federal law.”

“But critics charge the guidelines will be far too restrictive, making it difficult for some patients to be treated with the most effective options. There is also concern that the guidelines, which are not binding, will be widely adopted by state legislatures and government agencies.”

“These objections began percolating after the CDC disclosed the guidelines last fall. Earlier this month, the National Institutes of Health’s Interagency Pain Research Coordinating Committee met and decided to file an objection to the CDC. In particular, many of the participants expressed concern that the CDC relied on what was termed weak evidence for some of its recommendations.​​”

For full report from STAT news, see ​

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

23 Dec, 15 | by EBM

By Dr. Geoffrey Modest

The CDC just came out with draft guidelines for prescribing opiates for chronic pain (see!documentDetail;D=CDC-2015-0112-0002​ ). These draft recommendations include the following regarding when to initiate or continue prescribing opiates.

  1. Nonpharmacologic therapy and nonopioid meds are preferred for chronic pain. There are no data supporting chronic opiates, so hard to recommend given their known risks, except for this little caveat: “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, ands 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 CBT, 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 and heart especially, and significant mortality), but I should add that some of these drugs (e.g. salsalate) are off the Medicare-approved list for unknown reasons, are benign, but sometimes work 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 pain 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…)
  2. Before starting opioids for chronic pain, prescribers should establish realistic treatment goals with patients in terms of pain and function. This applies to pain lasting >3 months or past the time of normal tissue healing
  3. There should be periodic discussions with patients taking opioids about the 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
  4. 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). 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 [not-so-scientific] data finding more deaths with methadone, that should not be the first agent to use for a long-acting one.
  5. Use the lowest effective dose of opiates. And especially if increasing the dose to >50 morphine milligram equivalents (MME)/day. And “generally 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 longterm. 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 above dosage restriction, 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 may be genetic variants in mu receptors – 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.
  6. Chronic opiate use begins with acute pain therapy. So, for acute pain, we should also give the lowest dose possible and shortest duration of immediate-release opiates (and ERs should not blithely prescribe opiates). And “3 or fewer days usually will be sufficient for most nontraumatic pain not related to major surgery”. The 3-days 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.
  7. Evaluate benefits and harms within 1-4 weeks of starting opiates and at least every 3 months thereafter. 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.
  8. Before starting and periodically thereafter, evaluate risk factors for opiate-related harms.
  • 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
  • Again, 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: important people involved in prescribing and monitoring those on opiates are not allowed access, at least in Massachusetts, such as nurses, nurse practitioners/physician assistants; the pharmacy data are not updated as quickly as 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 (hence the benefit of giving nurses access….).
  2. 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
  3. 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)
  4. Arrange treatment for patients with opioid use disorder (e.g. with methadone or buprenorphine). 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, as with PDMP, 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 because 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 are dangerous both to the patient and society (through diversion, availability in the streets, overdoses, crime). 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, 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, ……..)


For other blogs: shows that teens given legit prescribed opiates are more likely to misuse opiates later in life finding unclear benefit of giving opiates 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)​ 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: HIV Therapy Without NRTI’s

23 Dec, 15 | by EBM

By Dr. Geoffrey Modest

The vast majority of recommended HIV drug regimens include tenofovir (TDF)/emtricitabine (FTC) or abacavir (ABC)/lamivudine (3TC) as the nucleoside/tide reverse transcriptase inhibitor (NRTI) backbone. From the 2015 HIV guidelines (see for review) ​of the 5 initial recommended regimens, all have NRTI backbones: 4 include TDF/FTC and one has ABC/3TC. Similarly, of the 2 NNRTI-based (non-nucleoside reverse transcriptase inhibitor) and 4 PI-based (protease inhibitor) alternative regimen options, 5 have TDF/FTC and 1 has ABC/3TC as the backbone; and of the “other regimen options”, 5 have either ABC/3TC or TDF/FTC. For those “who cannot have TDF or ABC”, there is only one which is NRTI-free: darunavir/ritonavir (DRV/r) plus raltegravir (RAL), with the caveat not to use if the HIV viral load is >100K copies/ml. For treatment-experienced patients, they recommend at least 2 and preferably 3 fully active agents. They comment that a boosted PI plus an INSTI (integrase strand transfer inhibitor) may be a viable option in patients with no INSTI resistance​, as the only mention of an NRTI-free regimen. So, almost all of the studies and recommendations include an NRTI backbone. In this light, there was a recent article looking specifically at the efficacy of NRTI-free regimens in treatment-experienced patients failing therapy (See Ann Intern Med. 2015;163:908-917).


  • 360 people (26% women, median age 46, 32% white/41%black/23% hispanic, 80% with HIV viral load <50K, median CD4 of 207, 47% with AIDS) who were treatment-experienced with HIV infections and had viral resistance (though 66% were sensitive to TDF, 30% to 3TC, 29% to FTC, 40% to AZT, 49% to ABC) from 2008-2011. All had been on PI-based therapy and had either used or were found to be resistant to some NRTIs and NNRTIs.
  • Put on open-label optimized regimens not including NRTIs, based on treatment history and resistance testing, then were randomized to adding or omitting NRTIs.
  • For the optimized regimens, they assessed the cPSS (continuous phenotypic susceptibility) score, a research tool to measure antiretroviral activity, making sure it was greater than 2 (this score is the sum of the scores of the individual agents used, where a score of “1” signified that the HIV was susceptible to the drug, “0” if resistant, and the continuum from 0-1 if there were partial resistance, reflecting the degree of resistance from the upper limit of “non-resistant” to the lower-limit of “resistant” — see their Appendix Table 1 for details).
  • 93% completed a 48-week visit


  • ​The optimized regimens turned out to be: RAL (raltegravir)+DRV/r(darunavir/ritonavir)+ETR (etravirine) in 56%; RAL+DRV/r+MVC (maraviroc) in 14%, and about 8% each to RAL+DRV/r+ETR+MVC, RAL+ETR+MVC, RAL+DRV/r+ETR+ENF (enfuvirtide), or other
  • ​The added NRTI mix was 81% TDF+(3TC or FTC); 14% TDF+(3TC or FTC)+AZT; 6% other
  • Cumulative probability of treatment failure was:
    • 8% in the omit-NRTI group vs 25.9% in the add-NRTI group (nonsignificant)
    • No difference in  primary safety endpoints or % of people achieving HIV viral load <50 copies/ml
    • No deaths in the omit-NRTI group vs 7 in the add-NRTI one
  • Conclusion was that it’s okay to omit NRTIs in these patients starting a new optimized regimen, thereby reducing pill burden, cost, and toxicities.

So, this is a useful article for patients either with broad HIV resistance to NRTIs, or to patients who are intolerant of them (and I have had one treatment-naive patient who pretty clearly developed a neuropathy to 3TC, thereby eliminating virtually​ all of the current and past recommended initial therapies). The basic approach in the past was to include NRTIs, even if there were resistance (e.g., continuing the pressure of 3TC on the virus in patients resistant to 3TC selected a less-fit and less-aggressive virus). This article shows that with our newer and better and easier-to-take and tolerate regimens, there is no compelling reason to add an NRTI-based backbone, even though a pretty good % of the patients in this study were in fact not resistant to them.

Primary Care Corner with Geoffrey Modest MD: Antibiotic Resistant Bugs in Gut Microbiome of Kids

22 Dec, 15 | by EBM

By Dr. Geoffrey Modest

Ciprofloxacin​-resistant e. coli are increasingly found worldwide and are capable of causing extraintestinal infections, especially urinary tract infections. A report in 2006 found that 1.5% of healthy Seattle children excreted cipro-resistant e coli in their stool, without prior fluoroquinolone exposure. A new study looked at 80 healthy children and their mothers​ who were part of the St Louis twin cohort, assessing stool samples from 2010-2013 semiannually from mothers, and monthly from their twins til age 2 yo and then bimonthly, analyzing for e coli resistance (see J Infect Dis. (2015) 212 (12): 1862-1868).


  • 15 kids (19%) and 8 mothers (20%) excreted ciprofloxacin-resistant e coli at least once, and 11 of 23 colonized subjects had multiple and usually consecutive positive samples
  • Overall 33% of 40 families had at least 1 member with a positive culture for cipro-resistant e coli
  • For the kids, the median day-of-life for the first positive specimen was 341
  • Stools specimens positive for cipro resistance correlated with length of hospital stay after birth (p=0.002), where the median was 6 days longer (10 vs 4 days) than for those with no resistance, and with maternal colonization (p=0.001); antibiotic use in the first 2 months of life, acid suppression, sex, mode of delivery or maternal perinatal antibiotic use were not correlated. and only 2 of the 15 kids with a positive stool specimen received any antibiotics at all in the first 9 months of life
  • In 6 families, both kids had positive stool samples
  • Cipro-resistant e coli were often resistant to other antibiotics: of 57 cipro-resistant e coli, 1 sample was resistant to 5 other antibiotics (ampicillin/cefazolin, tmp/smx, piperacillin/tazobactam, gentamicin, doxycycline), 5 were resistant to 4 of the other antibiotics, 16 to 3 antibiotics, 21 to 2 antibiotics, 8 to 1 antibiotic, and only 6 were resistant only to cipro
  • The cipro-resistant e coli had genotypes typical of extraintestinal pathogenic e coli.

So, some points:

  • Antibiotic-resistance is pretty common and may be increasing, even without the selection pressure of prescribed antibiotics
  • The cipro-resistant e coli found have the genetic profile of potential human pathogens (not just for urinary tract infections but also for soft-tissue and bone infections)
  • In this study they used a very small stool sample for inoculation, raising the issue of underestimating the actual presence of cipro-resistant e coli​ (and 1/2 the kids had only one positive stool sample, which may be because of the small inoculum and low levels of colonization)
  • Though there was a correlation between the length of hospital stays for the infants and subsequent positive stools, suggesting hospital-acquired colonizatons, the median date of the first positive culture was almost a year later​. One possible explanation is that these infants were in fact colonized in the hospital but their level of colonization was below what was detectable. Or, perhaps kids who stayed 6 days longer were more premature and there was something either developmentally or posthospitalization specific to these kids which led to more likelihood of acquiring the resistant bug. Not sure from the data.
  • So, how does this all fit together? Clearly the issue is common, probably increasing, and potentially quite profound, especially since the cipro resistance was almost always associated with resistance to other antibiotics, and we don’t have a slew of new, great antibiotics in the wings. The presence of resistance in kids without antibiotic exposure suggests, I think most likely, that there was community-acquired colonization, potentially from food (e.g. from animals or plants treated with antibiotics. Fyi, 80% of antibiotics used is for food production, and quinolones have been heavily used in agriculture and aquaculture for years). So, the canary in the mine whispers in my ear that we really try to understand the mode of spread of these resistant organisms (whether from food or community or hospital), to look at ways of restoring a healthy gut microbiome (through lifestyle interventions of diet/exercise — esp in adults, avoiding use of antibiotics or meds which put the microbiome at risk of pathologic changes), and largely to eliminate the unnecessary use of antibiotics in animals/plants and us.

For an array of prior blogs on antimicrobial resistance, see .

Primary Care Corner with Geoffrey Modest MD: Provider Computer Use and Patient Satisfaction

22 Dec, 15 | by EBM

By Dr. Geoffrey Modest

A small study was just published as a research letter looking at the impact on patient satisfaction when providers use computers in the exam room (see  doi:10.1001/jamainternmed.2015.6186.). This was an observational study done from Nov 2011 to Nov 2013 in an academic safety-net public hospital in San Francisco.


  • 47 patients (mean age 56.5, 55% women, 57% Hispanic/17% African-American/15% Asian/6% white, 55% primary Spanish speakers, 54% with high school education or less, 30% with inadequate health literacy as determined by their ability to fill out medical forms), and 39 clinicians (mean age 43.7, 64% women, 72% in primary care, 72% MDs, mean 13.9 years since getting professional degree)
  • Provider-patient relationship was <1 year in 16%, 1-5 years in 54% and >5 years in 30%.
  • Mean visit length was 24.6 minutes
  • Clinician computer use was low in 27% of encounters, moderate in 38% and high in 35% (this score was compilation of time reviewing computer data, typing or clicking with mouse, lack of eye contact with patient, and noninteractive pauses)
  • Rapport building included positive (laughter or agreement), negative (criticism or disagreement), emotional (empathy or partnership), and social (“chit-chat”) behavior
  • Encounters were videotaped and analyzed


  • Patients’ views in encounters with high computer use vs low:
    • Care was rated as excellent in 48% vs 83% (p=0.04)
    • There was more social rapport building by the patient (e.g. “you are wearing your hair that way…”; p=0.04) [though the authors note that in these high computer use encounters, this may not come across as “authentic engagement” and may lead to missed opportunities for developing deeper patient connections]
  • Patients in encounters with moderate computer vs low, computer use had less positive rapport building (e.g. “thank you”) (p<0.01) but had more positive affect tone (p=0.02)
  • Clinicians in encounters with high computer use:
    • ​Engaged in more negative rapport building (e.g. “no, it looks like your specialist filled that medication for you, it has a refill”; p<0.01)
    • ​Demonstrated less positive affect

So, as we head more and more towards computers being an integral part of the encounter (ménage-a-trois), there are some very real concerns:

  • It is really clear to me that it is in the history-taking that the vast majority of diagnoses and treatments are based
  • And, a therapeutic provider-patient relationship is really important in patient outcomes (and, I think, really very important in provider satisfaction as well)
  • But a computer intervening in this relationship, not surprisingly, undercuts these:
    • The computer systems I have seen (which are several of them) require focusing on the screen and, to some extent, pursuing questions as dictated by the screen. This is because much of the input is not free-text writing (which some of us can do without looking at the keyboard/screen), but navigating to sections of the screen, pushing on buttons there or filling in specific areas of the screen. And to the extent we are pursuing questions as dictated by the screen, we are not using the extremely important and often fruitful open-ended questions and then following up on the patient answers
    • There is much more information to process than in the good (and bad) old days. The good part is that we have the consultant notes, lab reports, results of ER visits right there. The bad news is that we spend a lot of time looking at these results, leaving less time to focus on the patient in front of us (and, overall it is probably better care to have quick access to all of this information, and in a way that is readable, as opposed to the old written medical records. But there is a price to be paid in terms of time and attention to the patient….)
  • So, what can be done?
    • I think that, at a minimum, it is useful to spend the first 5 or so minutes of the encounter just talking to the patient and having consistent eye contact.
    • ​And, of course, I think it is fundamentally absurd that those of us in primary care, who deal with pretty much all of the patients medical and psychosocial issues, have so little time to spend with the patient — to get to know the patient as a person and develop a caring relationship, get a good and accurate history, be able to help the patient to the extent we can, and to avoid unnecessary (and quite costly) visits to the ER or specialists for patient needs we could have taken care of in the first place.

Primary Care Corner with Geoffrey Modest MD: Empaglifozin, the good and the bad

21 Dec, 15 | by EBM

By Dr. Geoffrey Modest

A recent study looked at the SGLT2 inhibitor (sodium-glucose cotransporter 2) empagliflozin and cardiovascular outcomes/mortality in patients with type 2 diabetes (see N Engl J Med 2015;373:2117​). The SGLTs are involved in active renal transport of glucose in the kidneys, and SGLT2 is the most important one (reabsorbs 90% of the glucose filtered by the glomeruli) and seems to be pretty kidney-specific (SGLT1 is less important in active glucose transport, getting the remaining 10%, and is more widely expressed and therefore more likely to have broader physiologic effects and adverse effects if blocked). The context of this study is that there are a slew of studies showing markedly increased cardiovascular (CV) mortality in patients with type 2 diabetes, this relationship seems to be dose-related, and the increase extends to those with pre-diabetes/glucose intolerance. Other studies have shown that empagliflozin is associated with weight loss, reductions in blood pressure, increases in both LDL and HDL, and decreases in arterial stiffness/vascular resistance, visceral adiposity, albuminuria, and plasma urate levels (all of these might contribute to CV disease).

Details of the current study:

  • 7020 patients (mean age 62, 72% white/22% asian/18% latino, BMI 30.7, A1c 8.08%, 74% on metformin/49% insulin with mean dose 52 units/43% sulfonylurea/11% DPP-4 inhibitor/4% TZD, 95% hypertensive, 80% on lipid-lowering therapy. 83% on aspirin), all with established cardiovascular disease, all with A1C=7-9 and not on meds for >12 weeks or A1C=7-10% and on stable diabetes meds for >12 weeks). Subjects were randomized to empagliflozin 10mg, 25mg, or placebo daily, followed 3.1 years
  • Excluded: BMI >45, eGFR <30,  fasting glucose >240, ALT >3x upper limit of normal


  • 4% prematurely stopped the study drug (similar to placebo)
  • Weight decreased with med from 86 to 84 kg, waist circumference from 105 to 103 cm, SBP from 135 to 132 mmHg, DBP from 76 to 75 mmHg, LDL increased from 88 to 90 mg/dL and HDL from 44 to 46 mg/dL, uric acid decreased from 6 to 5.7 mg/dL
  • In the group on placebo, 31.5% had changes in their other diabetic meds, esp. sulfonylureas (increased 3.8% in those on empagliflozin and 7.0% on placebo), insulin (11.5% vs 5.8%), TZD (not sure which used, but increased 2.9% vs 1.2%), DPP-4 increased (8.3 vs 5.6%)
  • A1c was about 0.5% lower in those on empagliflozin, though there were changes as noted in other diabetic meds given
  • ​Primary outcome (composite of death from CV causes, nonfatal MI or nonfatal stroke) in 490 of 4687 (10.5%) of those in the pooled empagliflozin groups, vs 282 of 2333 patients on placebo (12.1%), so HR 0.86 (0.74-0.99; p=0.04)
  • No difference in rates of MI or stroke, but a lower death rate from CV causes (3.7% vs 5.9%, relative risk reduction RRR of 38%), hospitalization for heart failure (2.7% vs 4.1%, RRR of 35%), and death from any cause (5.7% vs 8.3%, RRR of 32%)
  • No difference in secondary outcome (primary outcome plus hospitalization for unstable angina)
  • Adverse events: increase in genital infections (5% in men vs 1.5% on placebo, 10% in women vs 2.6% on placebo). Rest nonsignificant.

So, a few issues (many of which were buried in the supplemental materials, which seems to be happening a lot in the past few years and my guess is that relatively few readers delve into these details, in part because it is a hassle, in part because it requires full, and expensive, access to the journals, and also is on the internet only. BUT it is often hard to really interpret the studies without seeing them…)

  • Of the very significant difference in CV deaths (5.9% in placebo and 3.7% with empagliflozin), the largest single category was “other cardiovascular death” (2.4% vs 1.6%) which “includes fatal cases that were not assessable due to a lack of information and were presumed to be cardiovascular deaths as per conventional definition”. And much smaller numbers of other CV events (acute MI in 0.5 vs 0.3%, worsening in heart failure in 0.8 vs 0.2%, stroke in 0.5 vs 0.3%). these increases in “presumed” events really undercuts the significance of the cardiac effect, especially in light of the very small numbers of events in these very high risk patients over >3 years of follow-up
  • The beneficial effects of the empagliflozin were within 3-6 months overall, a very rapid change. This makes the change in A1C from increased excretion of glucose in the urine an unlikely candidate for the CV benefit, and perhaps a quick change in arterial stiffness is more likely, or a decrease in arrhythmias for unclear reasons (sudden death was the most common single cardiac death event, with 1.6% in those on placebo vs 1.3% in those on empagliflozin). But one might imagine an even more profound cardiovascular benefit by having more of the patients on statins (only 76% of this really high risk population were on statins!!!)
  • Unclear what thiazolidinedione was used. Rosiglitazone??? (Which has more CV events). Subgroup analysis did find a nonsignificant trend to increased CV death in those on TZDs overall, though the interpretation really depends on which is being prescribed (pioglitazone may actually decrease cardiovasc events, see next point)
  • I think the study was not really accurately framed. their comment that evidence of lowering blood sugar “reduces the rate of cardiovascular events and death has not been convincingly shown” in fact does have some reasonable support for a few agents:
    • Metformin in UKPDS: there was a 16% reduction in cardiovascular complications — combined fatal or nonfatal MI and sudden death with metformin (p=0.052), was borderline significant. In a further analysis, patients allocated to metformin, compared with the conventional group (including insulin and sulfonylurea), had risk reductions of 42% for diabetes-related death (p=0·017), and 36% for all-cause mortality (p=0·011) (seeLancet 1998; 352: 854)
    • A large VA study compared monotherapy with sulfonylureas and metformin, finding a 21% increased hazard ratio for CV events or deaths in those on sulfonylureas vs those on metformin (see Ann Intern Med. 2012;157:601-610.)
    • Pioglitazone: in the PROACTIVE study, the main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0·84, p=0·027) (see Lancet 2005; 366: 1279)
  • Not to surprise you too much, but the cost of this drug is actually a lot: $5000/year with very low absolute benefit
  • And, within days of release of this article, the FDA released a warning for SGLT2 inhibitors (see, noting the risks for ketoacidosis and serious urinary tract infections. Updating their May 2015 warning, the FDA noted that 73 cases of diabetic ketoacidosis and 19 cases of urosepsis and pyelonephritis that started as UTIs have now been reported in patients taking these drugs, with some needing ICU treatment and dialysis (and this undoubtedly does not include all cases). So, be aware of these issues and stop the med/treat promptly​. They are now requiring postmarketing safety studies for 5 years.  But, as noted in prior blog , <20% of required postmarketing studies for medical devices were done within 3 years of the FDA requiring them, and no fines have been issued for noncompliance with the FDA mandates.  Also, as a point of reference regarding the DKA issue: noted the increase in ketoacidosis with SGLT2 inhibitors, with 1/2 the cases without any typical DKA triggering factors (e.g. infection), events happened in some with only very mildly elevated blood sugars (including <200 mg/dL), and ketoacidosis ranged  from 1-175 days after starting the med.

So, what is one to do??? As many of you may be aware, I am pretty hesitant to jump on the bandwagon of new drugs, especially when we have drugs that work pretty well. There are a lot of questions above about this study, ranging from what additional drugs were used in the placebo group (more sulfonylureas, which don’t seem to have much CV benefit and may even have some harm; and ??rosiglitazone — unclear if this was used). Also the likely mechanism of action was not by lowering the A1c, given the rapidity of decreasing cardiovascular events, so is this the best drug to achieve the benefit? Should more people be on statins? And SGLT2 drugs are not necessarily benign (hence the FDA warning).​

Primary Care Corner with Geoffrey Modest MD: Hip Arthritis vs X-Rays

18 Dec, 15 | by EBM

By Dr. Geoffrey Modest

2 cohort studies (the Framingham Osteoarthritis Study, a local community-based study, and the Osteoarthritis Initiative, a multicenter longitudinal study, assessed the correlation between hip pain and x-ray findings for hip osteoarthritis, or OA (see doi:10.1136/bmj.h5983).


  • Framingham Study: 946 ambulatory individuals >50yorecruited in 2002-5. All had hip x-rays, and those with hip pain pointed to where they had hip pain on a visual hip representation, the frequency of the pain, and they were examined for pain with internal rotation. Mean age 63.5, 56% women, 93% white, BMI 28, frequent hip pain in 13% though only 4% with pain in the groin or anterior thigh
  • Osteoarthritis Initiative: 4366 ambulatory people who had or were at risk for knee OA. All had hip films and if they had pain, had the visual hip representation to localize the pain, questions about frequency of pain but no examination. Mean age 61, 58% women, 80% white, BMI 28, 16% with frequent hip pain though only 4.5% in the groin or anterior thigh


  • Framingham data:
    • 6% of those with hip pain had x-ray evidence of OA
    • 7% of those with hip OA on x-ray had frequently painful hips
    • Sensitivity of x-ray diagnosis of OA for hip pain localized to groin was 36.7%; specificity was 90.5%, positive predictive value was 6.0% and negative predictive value was 98.9%
  • Osteoarthritis Initiative data:
    • 1% of those with hip pain had x-ray evidence of OA
    • 8% of those with hip OA on x-ray had frequently painful hips
    • Sensitivity of x-ray diagnosis of OA for hip pain localized to groin was 16.5%; specificity was 94.0%, positive predictive value was 7.1% and negative predictive value was 97.6%

So, there are several issues here:

  • For those with hip pain which is typical for arthritis, there is a poor correlation with x-ray And, this goes both ways: pain not related to x-ray changes and x-ray changes not related to pain. BUT, there is no clear gold standard for the definition of hip OA, a bit of a problem, though those with classic anterior groin pain worse with internal rotation and flexion seem like pretty good candidates for the diagnosis (and x-ray is not, since so many people have bad rays without significant symptoms).
  • A related issue is the lack of concordance between knee pain and x-rayUsing the NHANES I database, including 6880 people aged 25-74, there was also significant discordance between symptoms of knee pain and x-rays: radiographic stage 2-4 OA was found in 319 subjects (3.7%) and only 47% of these people had knee pain; knee pain was reported by 1004 people (14.6%) and only 15% had radiographic stage 2-4 changes of OA (see J Rheum 2000;27:1513-7)​. A recent analysis found that those with clinical knee pain but low OA grade on x-rays had heightened pain sensitivity (measured by Quantitative Sensory Testing, assessing pressure-pain thresholds at affected and unaffected sites to repeated and sustained stimuli) while those with low pain scores but high grade OA on x-ray were significantly less pain-sensitive, even after adjusting for age, sex, race, and psychosocial measures including depression, anxiety, pain catastrophizing (their word, not mine) and sleep disturbance (see Arthritis Rheum 2013; 65(2):.doi:10.1002/art.34646)
  • What does this mean?
    • ​We still may want to get hip x-rays in those with pain, to rule out osteonecrosis, transient osteoporosis, metastatic disease; and consider referred pain (though should not be reproducible by direct pressure/manipulation).
    • ​Pain is a funny thing. There clearly is not a one-to-one correspondence between pain and anatomic x-ray Lots of other factors play a role (including stress, sleep deprivation, depression, social supports, trauma history etc.)
    • So, we should not dismiss the diagnosis of hip OA based on normal or near-normal x-rays. The treatment is pretty much the same whether there are x-ray changes or not (weight loss, PT, pain meds). But the lack of x-ray changes should not dissuade us from the diagnosis of OA, nor potentially beneficial treatments (including intra-articular steroid injections)
    • But if the patient does have normal x-rays, I think it makes sense to review the history and PE to make sure that OA is still the likely diagnosis (as an aside regarding knee pain, I have had several patients sent to me for knee injections for OA, which on my exam has really been anserine bursitis. They still got an injection, but in a different place…. so, it makes sense to me to re-evaluate the pain when there is discordance of findings, just to be sure)
    • And it is not superclear what the role of MRI is. There is no question from the literature that MRI is more sensitive than x-ray, but likely is much less specific (this is pretty clear for knees, less clear for hips). But that being said, in those with significant functional impairment, clear indications that the pain is from the hip but only minimal arthritic changes on pain film, I would consider further workup for possible inflammatory synovitis, MRI to make sure it is not early osteonecrosis/avascular necrosis (if history of steroids, alcohol, pancreatitis, hemoglobinopathies, etc.) since early intervention (core decompression) can avoid later total hip replacement surgery, and consider MRI arthroscopy especially to look for labral tears, which are typically degenerative in those >50 yo and not responsive to conservative management.


Primary Care Corner with Geoffrey Modest MD: On-demand HIV Pre-exposure Prophylaxis

18 Dec, 15 | by EBM

By Dr. Geoffrey Modest

A recent trial looked at the effect of on-demand short courses of TDF/FTC (tenofovir/emtricitabine) in preventing HIV transmission in men at high risk (see N Engl J Med 2015;373:2237-46). There was a prior blog on pre-exposure prophylaxis from the PROUD trial, with continuous use of TDF/FTC, and included a brief report on the IPERGAY trial prior to publication — see​ . The full report on IPERGAY was just released, and I think it is so important that it is worth reviewing in some detail.

  • 400 men without HIV infection but who had a history of at least 2 encounters of unprotected anal sex with men ​within the past 6 months. Those with hepatitis B or C were excluded, as well as those with eGFR <60ml/min, ALT > 2.5 times normal, and glycosuria or proteinuria >1+ on urine dipstick.
  • Intervention: those randomized to active drug took TDF/FTC (300mg/200mg), 2 pills 2-24 hours prior to sex, then a third pill 24 hours later and a fourth 24 hours after the third, vs taking placebo. In cases of multiple sexual exposures, patients were instructed to take 1 pill/day until the last exposure, then 2 post-exposure pills. If there were exposure within 1 week of the last 4 pill dosing, then the patient took only 1 initial pill prior to the next exposure. All participants received risk-reduction counseling from a peer community member and condoms
  • Demographics: mean age 35, 90% white, 73% not in monogamous relationship/8% in a relationship with HIV-1 positive partner, 72% with postsecondary education, 45% used recreational drugs and 23% >5 alcoholic drinks/d. 5 enrollment sites in France and one in Montreal. followed median of 9.3 months
  • Results:
    • 56 of the patients received post-exposure prophylaxis (31 in TDF/FTC group, 25 in placebo)
    • Median of 15 pills taken/month in each group
    • ​Adherence — of 113 patients tested: 86% had TDF and 82% FTC in their blood, consistent with taking the med within the past week. TDF and FTC were found in 8 people on placebo, 3 of whom were on postexposure prophylaxis. Overall adherence: 28% did not take TDF/FTC or placebo; 29% took suboptimal doses, and 43% took the assigned drug correctly
    • No difference in sexual practices from before to during the study, though the placebo group did have a significant decrease in the number of sexual partners
    • 40% had a new sexually-transmitted infection during the study (20% got chlamydia, 22% gonorrhea, 10% syphilis, 1% hep C), confirming continued high-risk sexual practices
    • ​16 HIV infections happened after enrollment: 2 in the TDF/FTC group (0.91/100 person-yrs) and 14 in the placebo group (6.60/100 person-yrs), with relative risk reduction of 86% (36-97%, p=0.002)
    • The 2 HIV infections in the TDF/FTC​ group were in men nonadherent to pre-exposure prophylaxis (pill counts showed no meds taken and no meds were detected in the serum at the time of HIV diagnosis)
    • ​Adverse events: no significant difference in frequency of grade 3 or 4 adverse events (which were pretty much nonexistent), though there were more GI adverse events, esp nausea in 8% of those on TDF/FTC and 1% placebo and abdominal pain in 7% vs 1%. There was a transient decrease in eGFR to <60 in 2 people on TDF/FTC​

So, remarkably similar results to the PROUD trial with daily TDF/FTC. A few points:

  • These results are also similar to the iPrex trial (see Lancet Infect Dis 2014; 14: 820), which in their open-label extension found that those who had intracellular TDF levels consistent with taking at least 4 tablets/week had no incident HIV infections, very similar to the number of pills in IPERGAY (median of 15 pills/month), and adding to the validity of the IPERGAY results.
  • IPERGAY was a really short-term study, which not only may overestimate the effectiveness in clinical practice (over time, patients may become weary of taking meds each time they have sex) and underestimate adverse effects (too short a med exposure to see chronic renal disease, for example). Also raises the question of whether we need to monitor for adverse effects with intermittent dosing of TDF and how to do so (e.g., see blog​ on how to monitor TDF renal toxicity in those on daily TDF)
  • But it seems from all of the pre-exposure prophylaxis studies, that TDF/FTC works, and if you look at the subset of patients who actually take the drug, it essentially always works.
  • Overall, in these studies, there were not a lot of HIV infections, but it would be really interesting to know if this even regimen works in patients who have TDF or FTC resistant viruses, given that in some areas resistance is pretty common (i.e., useful to have a trial in a community of people with frequent HIV resistance mutations). It may well be that people need only a single active agent, so that the combo TDF/FTC would still work for many people in communities with resistant HIV infection. For example, in a South African study in women using tenofovir vaginal gel, there was a 54% lower rate of HIV acquisition in those who were high adherers to the treatment (see Science 2010;329(5996):1168) – i.e. using TDF only
  • It would be really useful to know if starting the TDF/FTC right after unprotected sex worked, since my guess is that adherence would be better than anticipating sex and remembering to take the pills at least 2 hours before.
  • Also, these studies with TDF/FTC were done in predominantly white, educated MSM communities, so would be useful to see how this on-demand approach works in poorer communities, in communities where the predominant spread is heterosexual or through drugs, and in minority communities. ​


I will add a comment from Jon Pincus about a blog sent out on the new release of meds with TAF (tenofovir alafenamide, which has less renal and bone toxicity, and is as effective as TDF) — see


So I know you don’t buy into big pharma conspiracies but……..


Odd that Gilead is releasing the combo pill long before the individual TAF or TAF/FTC pill.  TAF I believe is due for an FDA vote in April 2016.  


Coincidence that TDF patent is set to expire I believe in 2017 and that Gilead’s blockbuster single pill HIV drug, Atripla, was just bumped off its pedestal in the last Guidelines and is losing market share to triumeq [that is: abacavir/dolutegravir/lamivudine; and for the last guidelines, see​ for details]


All just coincidence I’m sure……

Primary Care Corner with Geoffrey Modest MD: Exercise Benefits in Elderly at Lower Levels

17 Dec, 15 | by EBM

By Dr. Geoffrey Modest

A couple of concerns about the exercise prescriptions we give patients: How realistic are they are for the elderly; and when older people cannot do the moderate-to-vigorous activities recommended, is there benefit in less aggressive exercise? A systematic review and meta-analysis was recently done to answer these questions (see doi:10.1136/bjsports-2014-094306).


  • 9 prospective cohort studies were found, with 122,417 participants (73,745 women and 48,672 men, mean age 72.9, average cohort size 13,602, six cohorts were American/2 from Pacific region/1 Asian, follow-up of 9.8 years and with 18,122 deaths (14.8%)
  • They defined 4 activity levels, by Metabolic Equivalent of Task, or MET) minutes: inactive, low (1-499 MET-minutes), medium (500-999) and high (>1000)
  • Results, with inactive being the reference:
    • ​Low activity had a 22% reduction in mortality [RR 0.78 (0.71-0.87), p<0.0001]
    • ​Moderate  activity had a 28% reduction in mortality [RR 0.72 (0.65-0.80), p<0.0001]
    • High activity had a 35% reduction in mortality [RR 0.665 (0.61-0.70), p<0.001]
  • Most of this association was for a reduction in cardiovascular disease (i.e. 25% reduction in low, 26% medium and 40% high activity), though the reduction in cancer mortality was also significant (ie 11% reduction in low, 16% medium and 31% high activity)
  • There was a dose-response curve, with more exercise intensity having more mortality benefit. But, the greatest decrease in mortality was associated with increasing from inactivity to the lowest level, with gradually more benefit as the intensity increases further.
  • Women benefited more than men: for those performing low activity exercise — men had 14% mortality reduction vs 32% in women (??do men overestimate their amount of exercise and women underestimate it??)

So, a few points:

  • For further clarification of METs and MET-minutes, see​ . As a rough guide: sedentary/resting energy expenditure is 1 MET; moderate activity is 3-5.9 METs, and walking 3 miles per hour is 3.3 METs; high activity is >6.0 METs, and running at 10 minutes/mile is a 10 MET activity.
  • Approximately 60% of older people cannot do 150 min of moderate-to-vigorous activity/week
  • These 9 studies were observational, though they controlled for many risk factors for mortality, such as smoking, blood pressure, fasting blood sugar, lipids, parental history of heart disease, etc. (e.g., see JAMA 1989; 262: 2395). Others of the studies in the meta-analysis also controlled for depression, mobility, chronic diseases, BMI, alcohol, education, diabetes, early parental mortality, and even red meat consumption — though it varied from study to study. The power of this paper is that it combines many studies with many participants showing mortality benefit from lower amounts of physical activity, and in that way gets a bigger picture of the results than a single study can. But, as with all observational studies, are there unanticipated confounders?? (i.e., are there other factors not taken into account which predispose some people to have less activity but put them at higher mortality risk? Perhaps they have unanticipated neurologic conditions? Or have they fallen and are afraid to do exercise, but are at higher mortality risk because of a condition predisposing them to fall?)
  • But, despite this significant limitation (i.e., not having a randomized controlled study with allotment of individuals to differing levels of exercise and seeing what happens), perhaps the strongest message we can give patients is: exercise is good for you and you should do whatever you can (the concern is that by prescribing/insisting on too much exercise for an individual, some people end up doing nothing). I have had success in just getting people to walk 15-20 minutes/day (15 minutes of walking/day is the midpoint of the low activity group, with 250 MET-min), and some of them are able to increase that over time. And many people actually feel better after doing exercise…

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