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Archive for December, 2016

Primary Care Corner with Geoffrey Modest MD: Drug shenanigans come home to roost (finally, at least a beginning)

19 Dec, 16 | by EBM

By Dr. Geoffrey Modest

There was a timely article in STATnews (in particular their Pharmalot series by Ed Silverman which regularly exposes drug company malfeasance) about price-fixing among generic drug makers. And, 2 generic pharmaceutical executives have finally been accused by the feds (see ). Hopefully more to come…

Jeffrey Glazer and Jason Malek of Heritage Pharmaceuticals, the former chief executive officer and president respectively, were accused by federal authorities of conspiring with rivals to fix prices for doxycycline hyclate and glyburide. This is the first criminal charges of a two-year federal investigation into such price-fixing among generic pharmaceuticals. At this point no other companies have been named, though Mylan Pharmaceuticals, Teva Pharmaceuticals, Actavis, Lannett Co, Impax Laboratories, Sun Pharmaceuticals, Endo International’s Par subsidiary, and Taro Pharmaceuticals have disclosed receding subpoenas in this investigation. These two executives had been fired from Heritage in August 2016 for a seven-year long “running criminal conspiracy that severely damaged Heritage”, noting that they had “looted tens of millions of dollars from Heritage by misappropriating its business opportunities, fraudulently obtaining compensation for themselves, and embezzling its intellectual property”, per the court documents. Heritage Pharmaceuticals claimed that these two had redirected more than $9 million to a dummy company between 2012 and 2015.

Prior findings have found that half of all generics had become more expensive during the prior 12 months, with 11 at least doubling the price, and one medication increasing 17,000%. This led to an investigation by Sen. Bernie Sanders of Vermont and Representative Elijah Cummings from Maryland, but the manufacturers have refused to testify (including Heritage), stifling the investigation. At that point Sanders had his formidable quote: “pharmaceutical executives must be held accountable for ripping off the American people by charging them the highest prices in the world for prescription drugs… At a time when one out of five Americans cannot afford the medication they need, we must do everything we can to end the greed and illegal behavior of the drugmakers. Fraud can no longer be an acceptable business model for the pharmaceutical industry.”

Also as reported by a prior issue of STAT and on a PBS news-hour blog on November 4, 2016 ( ) Sanders and Cummings want an FTC investigation into Eli Lilly, Sanofi, and Novo Nordisk, since their price for insulin has been going up in tandem over several years. The cost of insulin more than tripled from 2000 to 2013, from $231 to $736 a year per patient, despite the fact that the original insulin patent had expired 75 years ago.

There have been many blogs in the past on drug company shenanigans (see ). One ( ) commented on pyrimethamine but also mentioned the above Heritage increase in price of doxycycline from $20 for 50 tablets in October 2013 to $1849 in April 2014, an increase of  >8000%, leading many of us (including myself) scouring around for substitutes….

Tracking Guidelines’ Errors

19 Dec, 16 | by Kelly Horwood, BMJ

Tracking Guidelines’ Errors

Guest Blog Post
Authors: Primiano Iannone, MD, Monica Minardi, MD, James Doyle, MD
Institution: Emergency Department, Ospedale del Tigullio, Lavagna, Genova, Italy

Perspective: Wrong guidelines: why and how often they occur

Methods: Wrong guidelines: how to detect them and what to do in the case of flawed recommendations

Despite being used by most physicians to offer the best option of care for their patients, guidelines   can often suffer from serious flaws making them untrustworthy, even though considered evidence based tools.

We  identified three categories of guidelines’ untrustworthiness: 1) method related, when incorrect methods have been used (including inadequate management of conflict of interests, panel composition ; 2) content related, when there is discrepancy between recommendations and primary evidence which they refer to; and 3) outcome related, in the case of outcomes diverging from those expected by following the recommendation.  We considered quality of primary evidence against trustworthiness of guidelines, and  identified the need to set a trustworthiness threshold to be reached before adopting a recommendation as true, depending on quality of guideline and the amount of evidence available.  Furthermore, we searched the possible causes of guidelines’ untrustworthiness not only amongst the traditional factors commonly considered (conflict of interests, poor methods, panels not representing all of the stakeholders, lack of external and independent assessment of recommendations) but also with regards to the “waste” of biomedical research, as depicted by sir Iain Chalmers, which raises concerns regarding relevance of clinical research and coherence with existing knowledge. Additionally the lack of addressing  public health outcomes is considered.

Ultimately, we offered a “safety bundle” to help users to navigate guidelines with confidence, since current quality assessment tools (AGREE, GIN, IOM instruments) and guidelines repositories and databases do not express a quality rating which is directly useful in order to reliably discriminate between  right and wrong guidelines.

We identified and collected a substantial number of guidelines untrustworthy for either methods, content, or evidence of unexpected outcomes. We hope the readers will find this approach valuable in highlighting the awareness on flaws and errors, discussing guidelines trustworthiness hence cautiously interpreting their recommendations.



Primary Care Corner with Geoffrey Modest MD: Fluoroquinolone Warning

16 Dec, 16 | by EBM

By Dr. Geoffrey Modest

There was another FDA warning recently, this time regarding systemic fluoroquinolones (ciprofloxacin, levofloxacin, etc.), leading to a boxed warning, the FDA’s strongest warning (see for the summary, and for the full report).


  • Fluoroquinolones are associated with disabling and potentially permanent adverse effects on tendons (tendinitis, tendon rupture), muscles (muscle weakness or pain), joints (joint pain or swelling), peripheral nerves (peripheral neuropathy), and the central nervous system (anxiety, depression, hallucinations, suicidal thoughts, psychosis, confusion). Other adverse effects include worsening of myasthenia gravis, skin rash, sunburn (photosensitivity/phototoxicity), irregular heartbeat (including prolonged QT interval), severe diarrhea (they are the leading cause of Clostridium difficile-associated diarrhea). Multiple problems can occur in the same patient. The peripheral neuropathy may be irreversible.
  • Therefore, fluoroquinolones should only be used in patients where no other treatment options are available for acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and uncomplicated urinary tract infections. Also for serious bacterial infections where the benefits outweigh the risks.
  • The prior warnings for tendinitis, tendon rupture, and worsening of myasthenia gravis has been extended by the above problems.
  • Side effects may occur within hours to weeks after starting the fluoroquinolone and continue an average of 14 months to as long as nine years after stopping the medicines. (Though, as noted, some may be irreversible)
  • The majority (74%) of reported cases were in patients 30 to 59 year-olds, some with severe resulting disabilities. Most of the adverse reactions involve the musculoskeletal system, peripheral nervous system, and central nervous system. Long-term pain was most commonly reported symptoms, 97% of all cases reporting pain associated with musculoskeletal adverse effects
  • And one should stop treatment at the first sign of an adverse reaction


  • Although many of the musculoskeletal and central nervous system effects have been known for many years, the above update includes many other conditions. And some of the newly included conditions (e.g. peripheral neuropathy) can last forever.
  • My sense locally is that fluoroquinolones are still being used quite frequently for uncomplicated urinary tract infections and other relatively minor infections. Hopefully the above warning will further discourage their potentially unnecessary usages.
  • I’m also very concerned about antibiotic resistance overall, as many of you know. Please see for many blogs highlighting in rather scary detail the increasing antibiotic resistance in general, both in the US and worldwide. And I am also concerned about the effect of broad-spectrum antibiotics in particular and fundamental changes in the gut microbiome which can lead to many known, and probably many more unknown, health complications (see many blogs in )

Primary Care Corner with Geoffrey Modest MD: calcium intake does not increase cardiovascular risk

13 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent guideline from the National Osteoporosis Foundation and the American Society for Preventive Cardiology, with support from an independent evidence review team from Tufts University, determined that calcium supplementation, with or without vitamin D, had no relationship to cardiac health (for the recommendations see doi:10.7326/M16-1743; for the full document see doi:10.7326/M16-116).


  • calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) with the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time
  • Calcium intake should not exceed the National Academy of Medicine recommendations of 2000-2500 mg/d
  • Obtaining calcium from food is preferred to taking supplements
  • This recommendation is supported by a review of the human studies and is supported mechanistically and pathologically in animal studies on high-calcium diets (no biological mechanism supports the association between calcium intake and cardiovascular disease).


  • It is clear that calcium and vitamin D are necessary for adequate bone health. However several recent studies have questioned whether fractures were reduced by supplementation in older adults. There even have been reports that cardiovascular disease, including MIs and strokes, may be worse by supplementation (more below).
  • This review included 4 randomized controlled trials, one nested case-control study and 26 cohort studies.
  • Of note, very few studies looked at calcium intakes of greater than 1600 mg per day. One study that did do so, found that there was no increased cardiovascular disease (CVD) or mortality in those at the highest level of calcium by the combination of foods and supplements, but a somewhat increased risk in those on supplements only. However, for strokes there was a lower risk for all types of consumption.
  • There are several general concerns raised by all of these dietary studies:
    • They are usually dependent on dietary recall/food frequency questionnaires, often at only a few points in time, and dietary recall itself is not necessarily so accurate
    • It is really impossible in observational studies to isolate specific dietary ingredients or vitamins. Although analyses try to look at likely confounders, there are undoubtedly unanticipated ones (are those who have more calcium and vitamin D in their diet more likely to be health-conscious and also have a lower morbidity/mortality related to that? Or, contrarily, do those who are the least health-conscious take supplements to boost their calcium and vitamin D because they just heard on the news that this was important and might counteract their less healthy lifestyle?). It is interesting that in the one study with the highest levels of calcium intake, there was divergence between those who had calcium by foods versus supplements in terms of CVD and mortality. Perhaps those on supplements had generally less healthy diets? Or is there a fundamental physiologic difference between getting calcium from food versus pill (which appears to be different for CVD and stroke outcomes)??
    • The dietary studies themselves are often given equal weight, when some are better studies in others. For example, it is notable in the above that even the inconsistent association between calcium and/or vitamin D and CVD outcomes is more apparent in subgroup analyses than in the overall trials. And some showing lack of benefit for bone studied people with already adequate 25(OH)D levels to begin with (i.e. supplements might not do much more).
    • One cited concern is that increased calcium might lead to more vascular calcification. But this was derived from studies of persons with pretty severely impaired renal function on several meds, and not the general population.
    • As noted in prior blog (see ), there are real concerns about the value of meta-analyses/systematic reviews. Of course, there also limitations of single trials, or the latest trial that makes it into the journals and popular press. This current study was a truly independent meta-analysis, conducted by a well-respected group, and the evaluation of the individual studies they included pretty impressively confirmed that calcium intake is safe, even up to the 2000 to 2500 mg per day range (but the studies are pretty limited on this, as noted above).
    • The current meta-analysis did raise pretty serious methodologic concerns about 2 recently published reports finding adverse cardiovascular outcomes with calcium supplementation with or without vitamin D
  • There is also some confusion in the medical literature about the benefits of vitamin D in terms of fall prevention (see which critiques a recent study). The USPSTF most recent guidelines (prior to this study) still noted “that vitamin D supplementation is effective in preventing falls in community-dwelling adults aged 65 years or older who are at increased risk for falls”.

So, putting this all in perspective, I think that it is clear that bone health requires adequate vitamin d and calcium levels. Guidelines differ in their specific recommendations:

  • Some suggest achieving a 25(OH) vitamin d level of 20 ng/ml and some suggest 30 ng/ml.
    • The USPSTF in 2013 found insufficient evidence to recommend >400 IU vitamin D or >1000 mg of calcium (though it warns against supplementation with <= 300 IU vitamin D or <= 1000 mg calcium)
    • The Endocrine Society (see doi: 10.1210/jc.2011-0385) suggested checking 25(OH) vitamin d levels in people at high risk for deficiency, with deficiency defined as <20ng/ml (50nmol/L), and in general recommends:
      • For children <1yo, at least 400 IU/d; for 1-18 yo, at least 600 IU/d. but not enough reliable data to raise the 25(OH)D level to 30 ng/ml
      • For those 19-50yo, at least 600 IU/d, but might need 1500-2000 IU/d to achieve consistent levels >30 ng/ml
      • For those 50-70yo, at least 600 IU/d,but might need 1500-2000 IU/d to achieve consistent levels >30 ng/ml
      • For those >70yo: at least 800 IU/d. but might need 1500-2000 IU/d to achieve consistent level
      • For pregnant/lactating women, at least 600 IU/dbut might need 1500-2000 IU/d to achieve consistent levels >30 ng/ml
      • And more aggressive therapy (e.g. 2000IU/d) for those who are vitamin D deficient
  • For calcium, the NIH recommends (which is pretty similar to the Institute of Medicine):
    • Age 1-3: 700mg/d
    • 4-8 yo: 1000 mg/d
    • 9-19 yo 1300 mg/d
    • 31-70yo 1000 mg/d
    • But 51-70yo women and everyone >70yo: 1000 mg/d

I personally do suggest to patients that they consume a high calcium diet, but this is often limited by cultural or other circumstances (e.g., lactose intolerance). And, it is hard for those living in the Northeast to get adequate sunlight for adequate vitamin D levels (and I still shoot for 30 ng/mL as a target). So, though I would prefer all calcium and vitamin D coming from natural sources (diet, sunlight), most of my patients are on supplements. And usually taking 1 tablet of calcium 600mg combined with vitamin D 400IU twice a day is adequate (though I do have some high risk patients, including those with low Bone Mineral Density, who need 2000 IU of vitamin D/day). And I do check 25 (OH) vitamin D levels in those I think are at high risk (BMD, history of fragility fracture, medications, very limited outside sun exposure, etc.).

Recruiting for a new EBM Editor – 2017

13 Dec, 16 | by Kelly Horwood, BMJ

BMJ is looking for the next Editor(s)-in-Chief who can continue to shape Evidence-Based Medicine into a resource that offers the most up-to-date, clinically relevant, evidence-based content.

Read the full advert here >>

The candidate is an active scientist, who can demonstrate critical appraisal skills, an awareness of trends and hot topics in current clinical research and who will act as an ambassador; actively promoting and strengthening the journal and upholding the highest ethical standards of professional practice.

As Editor of Evidence-Based Medicine you will benefit from the following:

  • ● Competitive Annual Honorarium
  • ● Free subscription to EBM for you and your Editorial Team
  • ● Access to exclusive BMJ content, including The BMJ and BMJ Learning
  • ● Full training and support; from publishing processes to social media
  • ● The chance to shape the field and play a role in the development of the specialty
  • ● Have a positive effect on the careers of fellow scientists
  • ● Interact with the latest research from scientists based all over the world

International and joint applications are welcomed. Interviews will be held at BMA House. Term of office is 5 years; the role will take up in total one day a week. Contact Kelly Horwood for more information and to apply with a CV:

Application deadline: 9th January 2017

Primary Care Corner with Geoffrey Modest MD: Masked Hypertension

12 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent study compared clinic blood pressure (CBP) measurements and ambulatory blood pressure monitoring (ABP), finding much more masked hypertension than white-coat hypertension (see White-coat hypertension is when the CBP is higher than the ABP; masked hypertension is the opposite.


  • 888 healthy, employed, middle-aged individuals not on antihypertensive medications, found in a workplace screening program to have a blood pressure of <160/105 mmHg, then had 24 hour ABP.
  • Mean age 45, 89% female, 7.4% black/12% Hispanic
  • They compared the awake ABP (aABP), the CBP, and the difference. CBP was an average of nine readings over three visits after being seated a minimum of five minutes, and the participants had not smoked, eaten or had caffeinated beverages in the prior 30 minutes. Two other blood pressures were recorded 1 to 2 minutes afterwards. Those with CBP >140/90 were defined as having clinic-based hypertension, those with aABP >135/85 were defined as hypertensive. Those with elevated CBP but nonelevated aABP were defined as whitecoat hypertension. Those with nonelevated CBP but elevated aABP were classified as having masked hypertension.


  • Average systolic/diastolic aABP was 123/77 mmHg
  • Average CBP was 116/75 mmHg => average CBP was 7/2 mmHg lower than aABP
  • 3% were hypertensive by CBP; 19.2% were hypertensive by aABP; 15.7% with nonelevated CBP had masked hypertension. specifically,
    • For those with clinic blood pressure higher than ambulatory (white-coat), found overall in 17.8% by systolic pressure and 35.8% by diastolic:
      • Difference of > 5mmHg: 6.9% of subjects by systolic, 14.2% by diastolic
      • Difference of >10 mmHg: 2.5% systolic, 4.2% diastolic
      • Difference of >15 mmHg: 1.1% systolic, 0.9% diastolic
    • For those with ambulatory blood pressure higher than clinic blood pressure (masked), 82.2% of systolic and 64.2% diastolic
      • Difference of >5 mmHg: 63.7% systolic, 32.4% diastolic
      • Difference of >10 mmHg: 34.8% systolic, 9.2% diastolic
      • Difference of >15 mmHg: 14.4% systolic, 1.7% diastolic
    • This difference was most pronounced in young adults and those with normal BMI, decreasing at older ages and higher BMIs but did not disappear
    • No difference between men and women, black patients vs nonblack, Hispanic vs non-Hispanic, cigarette smokers vs past smokers vs nonsmokers


  • I had seen a few studies on masked hypertension with similar findings, but I must admit I assumed there was lots of hyperbole/biases to their conclusions, that white coat hypertension was undoubtedly much more common than masked hypertension. But — just goes to show you: for several patients their daily lives are even more stressful than the calm and relaxing clinician’s office….
  • This is clearly a flawed study in terms of drawing generalizable conclusions:
    • CBP was not really checked in a “clinic”, but at a workplace
    • As a workplace-based study, there is the “healthy worker bias” which not only selects people who tend to be healthier, but also selects people who may have somewhat higher social economic status (which itself seems to confer better health outcomes), as well as having few individuals over the age of 65. Of note only 5% of these people had elevated CBP, likely reflecting this healthier population.
    • The study did not include many nonwhite patients.
  • These biases clearly undercut the generalizability of the study’s results. Also, the high level of masked hypertension raises the question that more fit people (lower BMI) exercise more and have higher ambulatory pressures.
  • BUT, other studies have found masked hypertension in a wide array of patients (see Bobrie G. J Hypertension 2008, 26:1715) which found that the prevalence of masked hypertension was between 8 and 20%, and as high as 50% in treated hypertensive patients. A few studies mentioned in this meta-analysis found that masked hypertension was actually associated with 2 to 3 times the cardiovascular events than either white-coat hypertension or controlled hypertension in treated patients. In untreated patients, the data seems pretty mixed: studies varied between no increased cardiovascular risk to the same risk as untreated sustained hypertension. a couple of the studies:
    • The Jackson Heart Study (Diaz KM. American Journal of Hypertension 28(7) July 2015) looked specifically at African-Americans, finding that the prevalence of masked hypertension was 25.9% (34.4% in people with normal CBP) and that all of the surrogate markers of carotid artery intima-media thickening, left ventricular mass, and microalbuminuria were elevated (vs controls) in those with masked hypertension, and similar to those with sustained hypertension. They also found that male gender, smoking, diabetes, and antihypertensive medication use were independently associated with masked hypertension.
    • And, another study, the Dallas Heart Study (Tientcheu D. JACC. 2015; 66: 2170) assessed masked versus whitecoat hypertension and sustained hypertension in a group with 54% being African-American. They found a 17.8% prevalence of masked hypertension and a 3.3% of whitecoat hypertension. The risk for cardiovascular events over nine years was significantly higher in both the masked hypertension and sustained hypertension groups, but was barely significant in the whitecoat hypertension group, assessing cardiovascular outcomes. Controlling for an array of risk factors including clinic blood pressure measurements, they found that higher 24-hour ambulatory systolic and diastolic pressures were independent risk factors for new cardiovascular events. The adjusted relative risk for cardiovascular events was a 34% increase for each 1-SD increase in the 24 hour blood pressure, a 30% increase for ambulatory systolic blood pressure during the daytime and a 27% increase for ambulatory systolic blood pressure during the nighttime. For diastolic pressure the cardiovascular risk was 21% for each 1-SD increase for each, 24% for ambulatory diastolic pressure during the daytime and 18% for the nighttime. This graphs shows that there was essentially no relationship between clinic systolic pressures and cardiovascular events, that the correlation within each group of office-based blood systolics was only by ABP.


  • So, there are a number of questions that arise from these studies:
    • There is no clear consensus on how to define masked hypertension/what are the cutpoints? They used an ABP cutpoint of 135/85 mmHg as their definition of hypertension.  A consensus guideline suggested a 24-h average of >130/80, a daytime average of >135/85, and a night-time average of >120/70 (see O’Brien E. Hypertension 2013; 62: 988)
    • Are the clinical effects of masked hypertension really just those of increased blood pressure variability (see
    • Is there any real clinical advantage to identifying and treating patients with masked hypertension, and how?
    • How do we look practically for masked hypertension in our patients given that they have normal blood pressure in the office (assuming the studies suggest that identifying and treating these patients actually matters).

So, why, you might ask, am I bringing up masked hypertension, when there are no studies showing that unmasking it and treating it does anything???

  • I think it is always useful to hear about different information/perspectives which challenge the predominant ideology. The early studies on “mild hypertension” focused exclusively on clinic-based diastolic blood pressure. Then a few epidemiologic studies documented that systolic blood pressure was an even better predictor of cardiovascular events, moving the clinical target pressures into clinic-based full blood pressures. Then several studies either supporting or debunking the role of white-coat hypertension as important, and now, per my reading, suggesting that it is a little important but much less so than the other forms of hypertension. Then lots of studies on ambulatory blood pressure finding it to be much more predictive of clinical events than clinic-based blood pressure, and other studies showing that blood-pressure variability (either from clinic visit to clinic visit, or over the course of a 24-hour period) as being important. Now, over the past few years, emerges masked hypertension. We still do not know what to do with this, but there are a constellation of studies suggesting that this may be as important as sustained hypertension. But I think the real positive of this evolution in our thinking is that we are now situating hypertension in the realm of a person’s actual life instead of the artificial constructs of the clinic setting, and the data support this…
  • Masked hypertension fits in well with the increasing data on ABP as the predictor-of-choice for clinical events
  • It probably makes sense to think about masked hypertension in certain people, esp those with highish clinical blood pressure, since as in the above study, they are more liklely to have masked hypertension. Or in those with possible hypertension-related damage (e.g. retinal changes, LVH, renal dysfunction/microalbuminuria….) And, I think it makes sense to use the diagnosis of masked hypertension to reinforce the generally-useful-anyway lifestyle changes (diet, exercise, stress reduction…). I would be hesitant to prescribe meds for masked hypertension, lacking any real data on outcomes
  • And, as to how to measure it, it would be great to have ABP monitoring available and inexpensive. But, my completely untested hypothesis (though likely more practicable) is to use home-based or pharmacy-based measurements (which seems to be more accurate than CBP and approach that of ABP in the few studies done), with the clear prescription that the person should sit down/relax for several minutes, then check the numbers.

And, for the complete set of hypertension blogs, see

Primary Care Corner with Geoffrey Modest MD: Life expectancy decreases in the US in 2015

9 Dec, 16 | by EBM

By Dr. Geoffrey Modest

The CDC just released the life expectancy statistics for the US from 2015, finding a decrease of 0.1 years from the 2014 numbers (see  ).


  • In 2015, there were 2,712,630 deaths, an increase in 86,212
  • In 2015, life expectancy was 78.8 years, with 0.1 year decrease from 2014
    • For males, the decrease was 0.2 years from 76.5 to 76.3 in 2015
    • For females, the decrease was 0.1 years from 81.3 to 81.2 in 2015
    • For both, the change was only in life expectancy from birth, with no change in the group who made it to 65 yo [life expectancy for males aged 65 was 18.0 years, females 20.6 years: no change from 2014 to 2015. But no indication in their data as to why.  ??from more opiate deaths??]
  • The age-adjusted death rate increased 1.2% from 724.6 deaths/100,000 to 733.1 in 2015
    • This increase was highest for non-Hispanic white females (1.6%), then non-Hispanic white males (1%), then non-Hispanic black males (0.9%)
  • No change in 10 leading causes of death, but death rate increased for 8 of them and decreased for 1. (the 10 leading causes of death account for 74.2% of all deaths)
    • Increased for heart disease with age-adjusted death rate increase from 167 to 168.5, chronic lower respiratory disease (40.5 to 41.6), unintentional injuries (40.5 to 43.2), stroke (36.5 to 37.6), Alzheimer’s (25.4 to 29.4), diabetes (20.9 to 21.3), kidney disease (13.2 to 13.4), and suicide (13.0 to 13.2), but decreased for cancer (161.2 to 158.5)),
  • Infant mortality rate was no different, at 589.5/100K live births (was 582.1 in 2014, reflecting 240 more infant deaths, but the only significant change was an 11.3% increase in unintentional injuries
  • 10 leading causes of infant death were the same, though 2 changed rankings (maternal complications moved from #3 to #4 and SIDS from #4 to #3) in 2015

So, though life expectancy in the US has increased pretty dramatically since around 1970, and has had a largely linear increase in the past couple of decades, this new data is concerning (and more concerning if the trend continues). And there may be several impending changes in US policies in the next several years which could exacerbate this trend, potentially with more uninsured people without access to health care, a decrease in the social safety net which provides some basic needs to poor and disabled, changes in abortion laws (which in the past has led to maternal mortality associated with getting illegal back-alley abortions), perhaps increasing trends in interpersonal violence (which we are starting to see now), even perhaps too-early/more accelerated FDA approval of new meds and medical devices with potentially more adverse outcomes, increased pollution and health effects from possibly gutting the EPA and empowering fossil fuel producers/accelerating climate change, increased worker deaths from relaxed regulations, the adverse social and health effects of increasing income inequality, etc etc etc etc…… [not a pretty picture]

See and  which review studies showing that increasing longevity in the US tracks with income inequality

Primary Care Corner with Geoffrey Modest MD: FDA broadens indication for empagliflozin to include cardiovascular protection!!!

8 Dec, 16 | by EBM

By Dr. Geoffrey Modest

The FDA just extended the indication for the diabetes drug empagliflozin (Jardiance) to include reducing cardiovascular mortality in those with diabetes and cardiovascular disease. Their press release (see ) states that they looked at postmarketing data, though their original approval 2 years ago indicated that they requested 5 years of post-marketing data.

See my prior blog critiquing the original study leading to FDA approval ( )

Primary Care Corner with Geoffrey Modest MD: Light smoking and mortality

8 Dec, 16 | by EBM

By Dr. Geoffrey Modest

One increasingly common issue in primary care is what to say to patients who smoke only a few cigarettes a day. A recent observational study suggests that even smoking <1 cigarette per day as a consistent, long-term habit is associated with significantly increased mortality (see doi:10.1001/jamainternmed.2016.7511).


  • The National Institutes of Health – AARP Diet and Health Study is a huge database of 168,140 men and women aged 59 to 82 from 2004-2005 that has very specific information on cigarette smoking, including patient recall of their average number of cigarettes per day (CPD) during nine periods of time, starting with <15 yo to >70 yo (most of the time intervals were every 5 years until age 30 then every 10 years after that) along with number of CPD broken down into six categories (0, <1, then intervals of 10 CPD until 30, then >30 CPD). This database includes people from six states (California, Florida, Pennsylvania, New Jersey, North Carolina, Louisiana) and two metropolitan areas (Atlanta Georgia, and Detroit Michigan).
  • Mean age 71, 58% men. At the 2004-5 baseline, there were 22,333 current smokers/156,405 former smokers/111,473 never smokers. Mean follow-up 6.6 years, during which 37331 people died.
  • Of 19,853 current smokers with complete information, 1341 (6.8%) reported smoking <1 CPD and 6036 (30.4%) smoked 1-10 CPD at baseline.


  • Most people who smoked <1 CPD or 1-10 CPD at the 2004-5 baseline did smoke more CPD earlier in their lives. But, 159 (9.1%) and 1493 (22.5%) of these individuals reported consistently smoking those small amounts throughout their lives.
  • Lifelong consistent smokers with <1 CPD or 1-10 CPD tended to start smoking at a later age, were more likely to be non-Hispanic black or Hispanic, and have lower educational levels, less alcohol use, and less history of MI or emphysema.
  • As compared to never smokers,
    • Current consistent smokers at the baseline exam who smoked <1 CPD had a 64% increased all-cause mortality [HR, 1.64 (1.07-2.51)]
    • Current consistent smokers at the baseline exam who smoked 1-10 CPD had an 87% increased all-cause mortality [HR 1.87 (1.64-2.13)]
    • These associations were similar in men and women, and were found in an array of smoking-related causes of death, but especially strong for:
      • Lung cancer: HR 9.12 (2.92-28.47) for those who smoked <1 CPD; and HR 11.61 (8.25-16.35) for those who smoked 1-10 CPD.
      • Respiratory disease deaths: HR 6.00 (4.05-8.89) for those who smoked 1-10 CPD, but there were too few respiratory deaths in those smoking <1 CPD for statistical power.
      • Cardiovascular deaths: HR 2.78 (1.49-5.18) for those who smoked <1CPD; HR 1.50 (1.13-1.99) for those who smoked 1-10 CPD
    • The former smokers who had consistently smoke <1 CPD or 1-10 CPD, and those who quit at a younger age, had progressively lower mortality risks; those who quit after age 50 had a higher mortality, about 43% for each of these “light” CPD groups


  • Smoking is one of the biggest public health challenges, associated with 5 million deaths per year globally. It has also been found in several analyses to be the single most powerful risk factor for cardiovascular disease.
  • The issue of exposure to small amounts of cigarette smoke is increasingly common in the US. The percent of daily smokers who smoke <10 CPD has increased from 16 to 27% from 2005 to 2014. And, the percent of people who do not smoke every day has increased from 19 to 23%. However, there are studies finding that, especially in young people, they believe that low levels of smoking is safe.
  • In this study, as others, former smokers have a significantly decreased mortality as compared to current smokers. From other studies, these data are particularly robust for cardiovascular disease, where there is a dramatic decrease after about six months of smoking cessation. This may be in part because of the rapid decrease in the prothrombotic fibrinogen levels, which are really elevated in current smokers.
  • The authors make a strong point that smoking duration is associated with much more adverse health effects than smoking intensity. However, on my review of their references (including Flanders WD. Cancer Res. 2003:63(19): 6556), these studies did not look at those who had stopped smoking, where the cardiovascular effects (quickly, as above) and lung cancer affects (over about 15 years) revert to levels close to those of non-smokers. Also, in these old studies, people were smoking many more cigarettes than currently. However, it does make sense to impress upon current “light” smokers that duration of smoking is likely to be more important than the fact that they are only smoking a few cigarettes, and using this to reinforce the importance to quit.

So, my general approach previously had been to assume that even light smoking led to lung cancer, based on data from secondhand smoking studies, and that there is likely increased cardiovascular mortality, based on the fact that smoking even small amounts seems to rapidly increase fibrinogen levels (I have not seen robust data on this last point). The above observational study, however, gives pretty good support to the conclusion that even smoking fewer than one cigarette per day over the long-term is associated with increased all-cause as well as cardiovascular mortality. And, my experience in doing motivational interviewing even in these “light” smokers has been pretty effective.

Primary Care Corner with Geoffrey Modest MD: alpha blockers help with ureteral stone passage

7 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent meta-analysis/systematic review confirmed that a-blockers are efficacious in the treatment of patients with ureteral stones (see ).


  • 55 unique RCTs, with 5990 randomized patients, mostly in European and Asian subjects. Mean stone size 5.7 mm, tamsulosin was the a-blocker in 40 studies, mean follow-up of 28 days
  • Primary outcome: proportion of patients who passed their stone
  • Secondary outcomes: time to passage of stone, number of pain episodes, and proportion of patients who had surgery/were admitted to hospital/experienced adverse events


  • a-blockers facilitated the passage of stone, with risk ratio (RR)=1.49 (1.39-1.61), a 49% higher likelihood of stone passage (moderate qualityevidence)
    • The pooled risk difference was 0.27, meaning that 4 patients needed treatment for 1 to get benefit
    • The pooled % for stone passage was 75.8% in the a-blocker group vs 48.4% in the control group. this was basically independent of the type of a-blocker used or if imaging was done to assess stone passage
  • Subgroup analysis
    • No benefit for those with small stones, RR=1.19 (1.00-1.48), though on the cusp of being significant
      • Review of their figure of stone size:
        • Small trend to benefit if <5mm, increasing trend if <6mm
        • Reasonably clear benefit if >6mm, and esp if >8mm
      • In those with larger stones, RR=1.57 (1.39-1.61), a 57% higher likelihood of stone passage
      • No difference based on where the stone was located (upper or middle ureteral stones)
    • Secondary analyses, benefit of a-blocker:
      • Shorter time to stone passage, mean decrease of 3.79 days (3.14 to 4.45 days), moderate quality evidence
      • Fewer episodes of pain, mean decrease of 0.74 (0.21 to 1.28), low quality evidence
      • Lower risk of surgical intervention, RR 0.44 (0.37-0.52), moderate quality evidence
      • Lower risk of hospital admission, RR 0.37 (0.22-0.64), moderate quality evidence
      • Similar risk of adverse events, low quality evidence


  • This meta-analysis/systematic review follows on the tail of a recent RCT (see Pickard R. Lancet 2015; 386: 341), finding that neither tamsulsin4 mg nor nifedipine 30mg decreased the need for further intervention for stone clearance within 4 weeks of randomization. I am often concerned that we all tend to give disproportionate weight to the newest study. In fact this Pickard study, though a large one with 1136 patients, had 75% of them with stone size <5mm (which pass pretty easily on their own, and the above meta-analysis did not find much benefit to the a-blocker), and though the remaining 25% were >5mm, they do not indicate whether this was mostly 5.5mm or 9.8mm. And, likely because of the small size of the stones overall, 80% of the patients did not need any further urologic intervention in the ensuing month in either the intervention or control groups.
  • I should also reiterate the caveat that meta-analyses and systematic reviews are not the be-all and end-all, but are fraught with their own limitations, and are not considered very high on the evidence-based medicine hierarchy (and not even included in the pyramid of the most thoughtful pyramids, to my thinking. See )

So, bottom line is that this review does support the use of a-blockers in those with ureteral stones, especially if >5-6mm in size. There are also studies showing that calcium-channel blockers help (most studied being nifedipine), and the data are mixed as to whether the a-blockers or calcium channel blockers are better.

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