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Archive for September, 2015

Primary Care Corner with Geoffrey Modest MD: And the Drug Company Shenanigans Continue

30 Sep, 15 | by EBM

By Dr. Geoffrey Modest

I realize that I have blogged lots about drug company malfeasance/shenanigans. But they keep on coming and seem to be getting worse. Here is another from the NY Times on Daraprim (the brand name for pyrimethamine, a 62-year old drug used for parasitic infections, most notably for toxoplasmosis in HIV-infected patients but also occasionally for acute malaria) — see [Thanks to Paul Susman for bringing this to my attention].


  • Turing pharmaceuticals just acquired the drug and “immediately raised the price to $750 a tablet from $13.50”, though several years ago it was $1/pill. Of note, “Daraprim’s distribution is now tightly controlled, making it harder for generic companies to get the samples they need for the required testing”.
  • Also, cycloserine (used to treat multi-drug resistant TB) was recently acquired by Rodelis Therapeutics, which increased the 30-day supply from $500 to $10,800
  • The frequently-used antibiotic doxycycline went from $20/bottle in Oct 2013 to $1849 in April 2014
  • And, from NPR’s All-Things-Considered (see ), naloxone (Narcan, available since 1971), the main drug used to reverse potentially lethal opioid overdoses, is now a national focus in dealing with the opioid crisis (huge increases in the numbers of people trained to use it, large-scale programs to distribute and make free access to the intranasal form for opioid users, police, etc.) Injectable naloxone had been about $1/shot. The intranasal naloxone is made by only one company (Amphastar). NPR comments that in Baltimore, the price of naloxone in February of $20/dose jumped to $40/dose in July (thanks to sarah taylor for this reference).
  • And, speaking of opioids, though this is more an FDA and drug company joint shenanigans, oxycontin was just approved for kids over 11 years old (see for the FDA press release and for an editorial). However, there are several studies finding that children are at a higher risk of addiction than adults (see blogs in and a USA Today article ). My feeling on this is that there are some small numbers of kids who need chronic opioids for pain control, that fentanyl patches are already available, and that oxycontin has such a long history of abuse/addiction and is already being abused by kids (“1 in 25 high school seniors has abused oxycontin” per the USA Today report, the number of prescription painkillers has quadrupled since 1999, and >44,000 Americans die of drug overdoses every year). So, seems to me that the risks far outweigh the benefits (except for Purdue Pharmaceuticals, which is undoubtedly laughing all the way to the bank….)

Primary Care Corner with Geoffrey Modest MD: Aggressive Blood Pressure Management?

28 Sep, 15 | by EBM

By Dr. Geoffrey Modest

There was a thoughtful editorial in the NY Times by Eric Topol and Harlan Krumholz about the early release of results from the recent NHLBI-sponsored SPRINT study (Systolic Blood Pressure Intervention Trial), a trial which found that the target systolic pressure should be lower than in recent guidelines (see NIH release at ). The editorialists comment that this study as released does not have enough details to be useful, since it does not include specifics on the methodology and results to allow for adoption into practice (see ).  Here are the details of the study in brief, just for reference (I will not review this study until the full report becomes available).

  • 9300 participants >50yo with at least one extra cardiovascular risk factor (presence of clinical or subclinical cardiovasc disease other than stroke, eGFR 20-59, Framingham Risk Score with10-yr risk of >=15%, or age>75)​, randomized to a systolic blood pressure <120 vs <140 mmHg. Patients were recruited from 100 medical centers in the US and Puerto Rico
  • Study was expected to run 8 years until 2017
  • Study did not include diabetics, those with prior stroke, albuminuria> 600 mg/day or eGFR<20 (and a few other exclusions)
  • On average those with target systolic <140 were on 2 meds ; those with target of <120 were on 3 meds
  • The study was terminated early after only 6 years of the planned 8 years because of a 30% reduction in heart attacks and strokes, and a 25% reduction in deaths.
  • Primary results will be published “within a few months”. And more data will be collected over the next year to assess kidney disease, cognitive function and dementia

This is obviously an important study, since hypertension is so prevalent (79M adults in US, or 1 in 3, have high blood pressure and ½ of those treated for it still have systolic >140). However, I have real concerns about the early release of the above information, from which I think it is impossible to draw real conclusions for clinical practice. For example, there are no data on the actual numbers of people who benefit from the aggressive intervention (they include only relative risk reduction with no details on the absolute numbers of patients who benefited), we don’t even know what the achieved blood pressures were for the 2 groups, we don’t know what meds were used (i.e., were those on the 140 group on more b-blockers, which may be less effective clinically?), and perhaps most importantly they do not comment on the adverse effects of aggressive treatment (I have seen lots of people, especially elderly, who have significant orthostatic hypotension despite systolic blood pressures above 140, likely attributable to autonomic neuropathy. And I have real concerns about falls, esp. if the weather is hot, they do not drink enough, or they have diarrhea, etc. leading to even lower orthostatic blood pressures).

Topol and Krumholz comment that in this electronic age, it is essential for important study results to be available as soon as possible, but that the method of release needs to change: the preliminary details/raw data should be available for review to allow for a fuller understanding of the actual study and its clinical relevance. But, I think this suggestion should be a lot stronger, not just releasing the data (which may be hard for us in primary care to interpret fully). So, I would add a few points:

  • There actually has been an expedited process for decades, which worked quite well. The high-profile, high-relevance studies were released within 1-2 months (to my memory) in a complete form in the prestigious medical journals, along with editorials. It is quite striking to me the SPRINT study may not be released in a usable form for many months. I personally would be willing to wait the month or two to see the study in a clinically useful form. Perhaps this existing expedited process (now mostly as articles released “online first”) should be tweaked to accelerate the process a bit.
  • I am also very concerned about these high profile studies making it prematurely into the popular media, along with hyperbolic quotes from prominent physicians (in the SPRINT case, Dr Mark Creager, president of American Heart Assn, stated “it is outstanding news” in the NY Times on 9/12 — see My concerns are:
    • Patients who see these stories are likely to ask their providers for more aggressive blood pressure treatment, perhaps pushing us to treat some people inappropriately.
    • Providers may themselves think we should change our practice, given the enthusiasm of the “academic leaders” in promoting the trial, without our really knowing what happened.
  • Another side issue, especially since the vast majority of these “blockbuster medical studies” are funded by drug companies (the SPRINT study, at least from what I can discern, was not) is that sometimes the excessively long release could be used to the advantage of the drug companies. I don’t think I am too paranoid to wonder why the IMPROVE-IT study took 7 months for the final release. It was presented as the block-buster highest profile study of the American Heart Assn annual meeting (which, in every other case I know, comes out simultaneously in the New England Journal or similar journal); had even more initial superlative reviews in the general news media prior to its publication than the SPRINT study, supported by many of the big names in cardiology as a huge breakthrough; and led to a huge profit for this drug-company sponsored study by getting large numbers of people on ezetimibe, and once on it is likely to have these patients continue on this mediocre and expensive/profitable drug. See for my blog critiquing the study.

So, my bottom line is that important studies need to be released in a complete, interpretable form and as quickly as possible. The above NIH release, I think, does us all a disservice. It adds opacity and not clarity to an important and complex issue.  We’ll see what the study actually found in a few months…..​

Primary Care Corner with Geoffrey Modest MD: Heart Failure Outcome and CHADS-VASc Risk Score, Even if Not in Afib

24 Sep, 15 | by EBM

By Dr. Geoffrey Modest 

The CHA2DS2-VASc score is perhaps the best metric for predicting thromboembolic complications in patients with atrial fibrillation. This study assessed this tool for a variety of clinical outcomes in patients with heart failure, both with and without atrial fibrillation (see doi:10.1001/jama.2015.10725).


  • Danish registry study of 42,987 patients (all >50yo, mean age 75) with incident heart failure (HF), not on anticoagulation, of whom 21.9% had concomitant atrial fibrillation (afib), from 2000-2012
  • Assessed relation between CHA2DS2-VASc score and ischemic stroke, thromboembolism (TE) and death within 1 year of HF diagnosis


  • Patients without afib, risks of ischemic stroke was 3.1% (n=977), TE was 9.9% (n=3178), and death was 21.8% (n=6956), with stratification by CHA2DS2-VASc score (max=10)
    • Ischemic stroke: by CHA2DS2-VASc​ score of 1 through 6, the one year absolute risks were:
      • With afib: 4.5%,  3.7%, 3.2%, 4.3%, 5.6%, 8.4%
      • Without afib: 1.5%, 1.5%, 2.0%, 3.0%, 3.7%, 7%
    • All-cause death:
      • With afib: 19.8%, 19.5%, 26.1%, 35.1%, 37.7%, 45.5%
      • Without afib: 7.6%, 8.3%, 17.8%, 25.6%, 27.9%, 35.0%
    • At CHA2DS2-VASc score​>=4, absolute risk of TE was high regardless of presence of afib (e.g. for score of 4, 9.7% and 8.2% for those without and with afib)
  • The negative predictive value for ischemic stroke at 1 year post HF diagnosis was 92% (91-93%) in those with afib and 91% (88-95%) in those without afib

So, this study found that those with HF and without afib are at high risk of ischemic stroke, TE and death; the CHA2DS2-VASc score was helpful in stratifying these patients and had a moderately high negative predictive value as determined by 1 year post HF diagnosis; and those with CHA2DS2-VASc score​ >=4 had high absolute risk of TE (and even higher in those without afib than those with afib, though it seems that they only excluded those on anticoagulation prior to the HF diagnosis). On subgroup analysis, there was no association between female sex and increased risk of ischemic stroke, in patients both with and without afib (actually, of the individual components of the CHA2DS2-VASc score as noted below, female sex was somewhat protective in the group without afib and was not associated with ischemic stroke in those with afib. So, there seems to be differences depending on the individual components of the CHA2DS2-VASc score​.)

In general, in patients with afib, a stroke risk of >1%/yr is typically used as the cutpoint in identifying benefit from anticoagulation (i.e., tends to outweigh risks); in this Danish study the risk of ischemic stroke in those without afib was approx 1.5%/yr with CHA2DS2-VASc score>1. However, it is important to comment that it is not clear what the cutpoint should be in those without afib, though there are other studies showing that those with HF without afib are at increased risk of stroke and TE, and that these clinical events are decreased with warfarin therapy.

One clear concern is that this study does not have data on the LV ejection fraction (EF). Are the ones with terrible EFs the ones who get TE? And, does the CHA2DS2-VASc​ score, which it seems would correlate mostly with vascular risk, just pick out those with ischemic cardiomyopathy/low EF (i.e., are those with low EFs, who are more likely to have embolic events because of LV clots and/or stasis, being identified by the CHA2DS2-VASc score, and really just the EF itself is important??).  There are some studies in the literature which suggest that those with definite HF (recent decompensation requiring hospitalization), that HF itself was a significant independent risk factor for stroke/systemic embolism irrespective of LV systolic function, with overall rate of stroke being 1.5-2.4%/year — perhaps related to the finding in those with HF without afib that there are higher levels of pro-coagulants and pro-inflammatory factors such as elevated b-thromboglobulin, thrombin-antithrombin III complexes, and D-dimers (see Clin Ther. 2014; 36: 1135-44)​.  Other studies have also found the CHA2DS2-VASc score predicted clinical events even in patients without HF: in a 4.1 years study of 20,970 patients who were discharged with a diagnosis of acute coronary syndrome without known afib in a Canadian registry, 453 (2.2%) had a stroke or TIA with an annual incidence >=1% in those with CHA2DS2-VASc score >=4 (e.g., see Heart 2014: 100: 1524-30).

Another concern is that those with HF and high ​CHA2DS2-VASc score but without afib on initial evaluation may actually have intermittent afib leading to the adverse clinical events. For example, identifying those with intermittent afib by an event monitor might find those at high risk for TE, allowing for targeted anticoagulant therapy.

So, bottom line: HF is a bad disease with 45-60% 5-yr mortality. This Danish study is an observational one, with a limited database (not have ejection fraction, or know if the patient smoked, or drank alcohol, or….). It seems to me that given the high incidence of HF and high mortality, there really should be a randomized control study using anticoagulation vs not in those with HF and no evident afib. And, perhaps as part of this study, it would also be useful to utilize event monitors to identify those with HF and intermittent afib to see if they might be the patients who really benefit from anticoagulant therapy.

Here is the CHA2DS2-VASc scoring system:


Primary Care Corner with Geoffrey Modest MD: Sleep Deprivation and Colds

11 Sep, 15 | by EBM

By Dr. Geoffrey Modest

There have been several articles finding an association between short sleep duration and various infectious diseases. The current study was a better-documented clinical trial supporting this (see SLEEP 2015;38(9):1353–1359). Details:

  • 164 healthy adults (94 men and 70 women, mean age 30) volunteered for the study
  • These volunteers were monitored for 7 consecutive days for their sleep duration and continuity, both by subjective questionnaires and by wrist actigraphy (which correlates well with polysomnography, the gold standard)
  • Then they were given nasal drops containing rhinovirus 39 and subsequently monitored for 5 days in a quarantined hotel. A “clinical cold” was defined if they were both infected and met the illness criteria (objective measures of mucous production and nasal congestion)


  • 124 of 164 participants (75.6%) were infected with rhinovirus (antibody measurements before and 28d after viral exposure, and daily nas
    al rhinovirus cultures)
  • 48 (29.3% of them) developed a clinical cold
  • Objective sleep duration (by actigraphy) was associated with an increased likelihood of developing a clinical cold, with odds ratios of developing a cold, as compared to those sleeping >7hrs per night:
    • <5 hrs/night had OR=4.50 (1.08-18.69)
    • <5-6 hrs/night had OR=4.24 (1.08-16.71)
    • 6-7 hrs/night had a nonsignificant  OR=1.66 (0.40-6.95)
  • These results were independent of prechallenge antibody levels, demographics (e.g. SES, education), season of the year, BMI, various psychological variables (e.g. perceived stress), and health practices (e.g. smoking, physical activity, alcohol)
  • Sleep continuity was not associated with developing a cold
  • Sleep duration was not related to getting the infection, just in getting sick


I bring up this study for a few reasons:

  • This study fits in with the very large literature on stress and diseaseover the past many decades, showing that both acute and chronic stressors, both physical and mental, can create huge changes in both hormones (essentially all hormones are affected), and in immunologic function (esp T cell and natural killer NK cell function), perhaps largely through the effects of the cortisol increases from the stressors. Of note, at least in several studies which directly looked at this: the issue is not so much the intensity of the stressor, but how the stressor is perceived by the person; and the physiologic effect of the stressor (including cortisol levels) is moderated by the degree of social support that the person has (not surprising that there are mediators to the effect of stress on individuals, since people exposed to the same physical or mental stressor often have different physiological reactions to it).
  • It brings up the limitations of the “germ theory”. Perhaps the main conclusion (to me) of this study is that infectious diseases (at least the vast majority of them) reflect a complex interplay between the characteristics of the bug and the host response to that bug. It is not just the presence of an external stimulus, but its interaction with the human organism.  Not everyone exposed to an organism gets infected (in this study 75.6% actually got infected, though this was not related to decreased sleep) and not everyone who gets infected develops disease (in this study 29.3% got a cold, which was related). In addition, not assessed in this study, there is great variability in the disease severity in those who get the disease, perhaps related to the individual’s immunologic response that is partly determined by the social environment. One summary article noted that even relatively acute sleep deprivation (less than one week) is associated with increases in cortisol, decreases in TSH, increases in prolactin, increases in growth hormone, and  increases in ghrelin/decreases in leptin, which might cause the munchies found with sleep deprivation (see, as well as the whole issue of the journal Brain, Behavior, and Immunity, volume 18, 2004 devoted to the hormonal/immunological effects of sleep deprivation​). Other studies have found sleep deprivation related to increases in inflammatory markers (e.g. C-reactive protein), down regulation of T cell production of interleukin-2, overall decreased proliferative capacity of T cells in vitro, and decreases in NK cells. Of interest, there seems to be a bidirectional association between sleep deficiency and inflammation, with studies finding that cognitive behavioral therapy for older adults with insomnia leads to decreased levels of systemic inflammation (Sleep. 2014; 37: 1543-52).
  • And, as the graph below showed, overall we are getting less sleep over the past 50 years.
  • The presumed association between disease and social conditions, by the way, has been articulated for a long time. For example, Virchow in 1879 wrote: “Don’t crowd diseases (epidemics) point everywhere to deficiencies of society?”​

Primary Care Corner with Geoffrey Modest MD: Snake Oil?

10 Sep, 15 | by EBM

By Dr. Geoffrey Modest

I have written a few recent blogs on the increasing laxity of regulation. One (see ) highlighted the use of implantable cardioverters, use of which has migrated from studies documenting benefit in less elderly stable ambulatory patients to implanting them in the unstudied older sick hospitalized ones, then finding no clear clinical benefit in this group. Another (see ) looked at the approval process for medical devices, which involves minimalist premarket studies often to be followed by FDA-required aggressive post-marketing follow-up studies which are mostly never done/printed. In this light, there was a truly scary article in New Engl J of Medicine this week (see  DOI: 10.1056/NEJMhle1506365). This article reviews the history of the FDA, its developing much more teeth in 1962, and the erosion of its power over the past few decades, culminating in the current pharmaceutical case as below.

  • The current case: in May 2015 Amarin (a small Irish drug company) sued the FDA to allow it to distribute information about the usefulness of its prescription fish oil product for an unapproved indication (lipid lowering), stating that such refusal violated its First Amendment right to free speech. The FDA replied in June with a conciliatory letter stating that most of the information was okay (also suggesting that the drug be reclassified as an unregulated dietary supplement… a topic for another blog). The company rejected that, went on with the lawsuit, and in August a federal judge sided with the drug company, citing its “‘considered and firm view’ that the FDA could not prevent promotion of a drug for an unapproved use if a manufacturer’s promotional statements are ‘truthful'”. [Note: one potential consequence is that patients might be prescribed fish oil for lipid management, without documented clinical benefit, instead of clinically-proven therapies. And, does a small drug company sponsored study showing some decrease in triglycerides qualify as “truthful” promotion for a clinical indication? And should that be determined in the court system?]

History (in very brief — the article is quite good on this)

  • FDA established in 1906
  • Until 1962, drug manufacturers were not required to demonstrate that a new drug worked
  • 1962 legislation: FDA was given authority to consider any drug labeling or promotional material that was not explicitly approved by the FDA as “false or misleading” and subject to fines. More than $15B in fines were levied starting in the early 2000s till the present against almost all of the drug companies for illegal off-label promotion (e.g. promoting use of antipsychotics in elderly with dementia to control behavior). The rationale for this legislation was that neither consumers nor physicians could be expected to determine drug effectiveness or safety without an extensive evaluation by the FDA scientists and advisors reviewing all the data
  • The erosion of FDA authority seems to have begun in 1980 (which, by the way, was when Reagan was elected…), when the Supreme Court took on a case by compounding pharmacies trying to avoid governmental oversight, the Court finding that the government did have a substantial interest in promoting public health by ensuring rigorous drug testing but also had an interest in facilitating patient access to the drugs. [The recent series of 11 infectious outbreaks caused by contaminated compounded meds affecting 207 and killing 17 was attributed to “inadequate regulatory controls”.]
  • There have been other recent examples: a drug rep successfully sued the FDA that promoting an off-label indication for a drug (sodium oxybate) was infringing on his right to free speech.
  • The FDA itself had been undercutting its own authority, and in Feb 2014 issued a draft guidance that would make it easier for drug companies to disseminated information about non-approved drug indications. This included allowing drug reps to distribute peer-reviewed studies that describe lower risks from the meds than what was determined by the FDA.

So, this brings up several issues:

  • The potential further degradation of the quality of the data: those studies, for example, which might show fewer adverse drug effects than the FDA documented in their broad review will almost always be sponsored by the drug companies (with their attendant well-documented shenanigans).  And, even if those of us in the trenches were aggressively trying to assess all of the relevant studies, we do not have access to many of them — esp the negative studies (though the FDA does)
  • A related issue mentioned in prior blogs: there is a huge concern with the large numbers of clinical guidelines, with a dramatic shift from governmentally- generated (e.g. NIH) to specialty society sponsored ones.  A JAMA study (JAMA 2009; 301: 831-41) found that of 16 guidelines released by the Am College of Cardiol and Am Heart Assn, 1/2 of the recommendations had evidence level C (expert opinion), and a large % of the guideline writers (i.e., experts) have significant conflicts of interest. (I am not just picking on cardiology — there are similar issues with lots of other specialty recommendations). A viewpoint in the Sept 1 2015 issue of JAMA notes that the Institute of Medicine considers the current approach to the development of clinical practice guidelines to be very flawed, in part from these often-unreported conflicts of interest. This is another issue diluting our ability to practice the highest quality medicine based on the best evidence.
  • And, the big issue: further erosion of FDA regulatory power, perhaps under guise of free speech for corporations (now considered to be “personlike entities” by the 2010 Citizens United case) could bring us back to the snake oil salesmen of old, and that neither we as providers nor the patients might be able to evaluate the studies well (pretty much all done by drug companies), which would dramatically undercut our ability to make sure that the benefit of meds are real and outweighs their risks.​


Primary Care Corner with Geoffrey Modest MD: Low Dose Aspirin and Colon Cancer Risk

9 Sep, 15 | by EBM

By Dr. Geoffrey Modest

The case for aspirin use for primary prevention of cardiovascular disease is a bit of a toss-up. However, there may be additional roles for aspirin (and NSAIDs) in cancer prevention (see doi:10.7326/M15-0039). Over the past 20-30 year, there have been many studies in animals showing a potential benefit of aspirin and NSAIDs in preventing colorectal neoplasia. And many observational studies in humans have found a reduced risk of colorectal cancer. More data is needed, though one of the lingering questions is the dose of aspirin associated with decreased colorectal cancer. This current study cross-references the Danish cancer registry with the pharmacy registry, with pretty complete data.


  • Population-based cohort study of people in Northern Denmark, comparing aspirin and NSAID use in 10,280 cases of documented colorectal cancer with 102,800 controls, between the years of 1994-2011
  • In Denmark, there is a pretty complete registry of patients with histologically-verified first diagnosis of colorectal cancer; also, >90% of total sales of low-dose aspirin are prescriptions and tracked in their systems. Of the NSAIDs, only ibuproben 200mg (15% of total Danish sales of NSAIDs) is over-the-counter, so the vast majority are tracked.
  • Median age 69.8, 54.8% male, 78% never used low-dose ASA, 54% never used NSAIDs, 12% on hormone replacement therapy, 15% statins, 7% diabetic, 20% with rheumatologic disease, 19% cardiovascular dz


  • Those continuously taking low-dose aspirin (75,100, or 150mg/d)  for >5 years had a 27% reduction in colorectal cancer risk [OR 0.73 (0.54-0.99)]
  • Those taking NSAIDs consistently for >5 years esp at the highest doses, hada 36% reduction in colorectal cancer risk [OR 0.64 (0.52-0.80)], and especially so in those NSAIDs with significant COX-2 selectivity
  • The data for ever-use (i.e., not taking continuously) was non-significant for aspirin, but significant for NSAIDs (6% risk reduction)

So, how does one piece this all together???

  • The data on cancer is largely from observational studies (and therefore susceptible to lots of biases), though the Danish one seems to be pretty tight. I am adding some of my older blogs at the end here, to reference some of these older cancer studies. It is notable that the aspirin data in the Danish study found potential effectiveness in those on low-dose aspirin. Their data on NSAIDs is also pretty strong and consistent with older data, though I would argue that NSAIDs have lots of other adverse effects (blood pressure, heart failure, renal failure…), and the most effective ones (COX-2 selective) are pretty consistently bad for the heart.
  • There have been several primary prevention studies in the use of aspirin for cardiovascular disease. Overall, the data, in this pretty low risk group (as opposed to secondary prevention studies) is: there is a significant 20% decrease [RR 0.80 (0.67-0.96)] in risk of first nonfatal MI, and non-significant decreases in total mortality and stroke, but a 54% increase in major extracranial bleeds [RR 1.54(1.30-1.82)] and a 12% decrease in cancer incidence [RR 0.88(0.80-0.98)]. For example these numbers translate to — for a 60 yo man over 10 years:
    • At low cardiovasc risk: 5 fewer nonfatal MIs, 4 more significant extracranial bleeds
    • At mod cardiovasc risk (eg 10-yr risk of about 5%): 17 fewer nonfatal MIs, 16 more significant extracranial bleeds, approx 1 more intracranial bleed
    • At high cardiovasc risk (10-year risk of about 10%): 27 fewer nonfatal MIs, 22 more significant extracranial bleeds, approx 1 more intracranial bleed
    • At low cancer risk: 1 fewer cancers
    • At mod cancer risk: 6 fewer cancers
    • At high cancer risk: 12 fewer cancers
  • As with most things patient-wise, it is useful to look at the individual instead of the aggregate data. Those in the primary prevention group who are healthy, active, have no risk factors, are at low risk for cancer, probably should not be on aspirin. Those on the opposite end of the spectrum (no cardiovasc disease, but smoker with lots of other risk factors; or at high risk of cancer) probably should be. All patients should get a sense of the risks and benefits, taking into account where they are in the spectrum of potential disease (heart has the best data, though I do include cancer risk) along with how they value potential outcomes (e.g. long-term potential protection from cancer and heart disease, esp nonfatal MI) vs risk of major bleed, including the much lower risk of intracranial hemorrhage.

Here are the older blogs: raises the issue of cancer prevention as part of the equation of its use in primary prevention has 2 studies: one showing decreased cancer mortality, the other decreased metastatic disease finding decreased ovarian cancer finding decreased prostate cancer metastases and mortality

Primary Care Corner with Geoffrey Modest MD: Weight Loss Decreases NAFLD

8 Sep, 15 | by EBM

By Dr. Geoffrey Modest

A recent Cuban study looked at the effects of weight loss through lifestyle modification and biopsy-proven changes in nonalcoholic steatohepatitis (See Gastroenterology 2015;149:367–378).

Background:Nonalcoholic fatty liver

  • NAFLD (non-alcoholic fatty liver disease) is probably the most common cause of abnormal liver chemistries throughout the world, with purported incidence of 15-40% (16% in the recent NHANES III data) and increasing dramatically over time (paralleling the increases in obesity and diabetes); NAFLD is often associated with obesity, metabolic syndrome, diabetes, dyslipidemia.​ NAFLD is definitely more common than hepatitis C at our health center, where we certainly see a lot of hepatitis C.
  • NASH (non-alcoholic steatohepatitis), a biopsy diagnosis, is the most advanced/aggressive form of NAFLD, and has the highest likelihood within NAFLD to progress to cirrhosis, liver transplant, and hepatoma. The risk of hepatoma varies in studies, e.g. from 2.4% over five years in one study and 12.8% over 3 years in another.

Details of study:

  • Prospective study of 293 patients with histologically proven NASH. Mean age 48.5, 41% male, weight 83.4 kg and BMI 31.3, 61% hypertensive, 52% hyperlipidemic, 33% diabetes, 33% prediabetes, ALT 52.4 U/L
  • Baseline histology: steatosis 33-66% in 48%, >66% in 23%; NAS score (NASH disease activity score) >4 in 60%; lobular inflammation in >1 focus in 41%; “many” ballooning cells in 58%; fibrosis stage 0 in 61%, 1 in 8%, 2 in 20% and 3 in 11%
  • All patients were encouraged to adopt lifestyle changes to decrease their weight over 52 weeks, during the time period of 2009-2013, consisting of dietary recommendations — low-fat diets with 750 kcal/d less than their daily energy needs (CHO 64%, fat 22% and <10% sat fats, protein 14%) and encouragement to walk 200 minutes/week. There were individual behavioral sessions to promote adherence to this every 8 weeks.
  • Paired liver biopsies were available for 261 patients, all of whom had fatty liver on imaging studies, persistent increase in ALT (for at least 2 consecutive visits), or risk factors for advanced disease (metabolic syndrome, >45 yo, obesity and diabetes). Men drinking >20g/d and women >10g/d alcohol for the previous 2 years were excluded, as well as those with evidence of other causes of liver disease. Diabetics had to have A1C<9%. Other exclusions include using meds felt to be insulin sensitizers (e.g. glitazones, vitamin E), prior use of hypolipidemic drugs (though they did use meds in those who continued to be hyperlipidemic after 3 months of lifestyle changes)


  • At 52 weeks, 30% lost >= 5% of their weight (10% lost >10% of their weight, 9% lost between 7-10%, 12% lost between 5-7%). Mean weight loss of 4.6 kg, corresponding to 413 kcal reduction in daily consumption, with 12.9% reduction in CHO intake and 14% reduction in fats. Physical activity score increased minimally (and there were no relationships found between physical activity and either weight loss or in liver histology changes). No difference in outcomes for weight loss by initial BMI or if diabetic or not
  • 25% achieved biopsy-proven resolution of their NASH
  • 47% had reductions in their NAS score by at least 2 points
  • 19% had regression of their fibrosis/65% were stable, 39% had improvement in ballooning score, 50% had improvement in lobular inflammation, 27% had improvement in portal inflammation
  • Degree of weight loss was independently associated with improvement of all NASH-related histologic parameters
    • Comparing those who lost >=5% of their weight to those <5%: 58% had NASH resolution and 82% had a 2-point decrease in their NAS (p<0.001). And all patients without baseline fibrosis who lost >5% of their weight remained fibrosis-free.
    • Those losing >=10% of their weight: 90% has resolution of NASH, 45% had regression of fibrosis and all had reductions of NAS
    • In females with BMI>35, fasting glucose >5.5 mmol/L (100 mg/dl), and many ballooned cells on biopsy, NAS scores decreased significantly with weight reduction >10% [I’m not sure why they singled out this group — I have never seen anything suggesting that females have a higher likelihood of progression of NASH. The major predictor of progression is the initial biopsy showing fibrosis or inflammation]

So, there was a graded decrease in NASH as weight loss increased, the maximal benefit in those able to loss >10%, and most of the patients with worsening fibrosis had little or no (<5%) weight reduction. this study was significant (to me) in that they achieved impressive weight loss overall in a real-world setting (i.e., without those irreproducible, aggressive study environments). This study did show that lifestyle-induced weight loss of >7% was associated with significant decreases in NASH activity, showing that achievable weight losses work and people do not have to get down to their ideal body weight to have dramatic effects. And, this study adds to the literature finding weight loss leads to decreases in NAFLD (see , for example, which looked at a noninvasive assessment of liver fat and found a graded effect of hepatic fat resolution with increased weight loss.) Also, there was a companion study in the same Gastroenterology journal as the Cuban study which assessed the effect of bariatric surgery, finding a year later that NASH resolved in 85% and fibrosis was reduced in 34% (see Gastroenterology 2015; 149: 379–388). Another implication of this study (as in other studies of hepatic fibrosis) is that fibrosis is not the fixed, irreversible scarring that we had learned in medical school (at least for those of us trained in the foregone dusky ages, if not the dark ones)

Primary Care Corner with Geoffrey Modest MD: H pylori Regimens

3 Sep, 15 | by EBM

By. Dr. Geoffrey Modest

BMJ just published a network meta-analysis of h pylori eradication by different regimens (see BMJ 2015;351:h4052). They identified 143 studies with 14 different treatments. Some varied by length of treatment, some by antibiotics used, some by addition of probiotics, and some by consistent vs sequential therapy.

Background (as noted in prior blogs):

  • H pylori  is associated with an array of GI issues (dyspepsia, PUD, gastric mucosa-associated lymphoid tissue lymphoma or MALT, gastric cancer), as well as Fe-deficiency anemia, ITP, and perhaps due to its systemic inflammatory effects, may be associated with neurologic disorders (alzheimers, parkinsons, stroke) as well as cardiovascular disease
  • H pylori is the most common human pathogen, infecting about 50% of the global population (about 30% in North America and northern Europe, higher numbers in Eastern Europe, South America, Asia, Africa)
  • The effectiveness of the initial standard therapy (PPI, clarithromycin, and amoxacillin or metronidazole) has decreased over time
  • Since there are no studies comparing multiple treatment strategies, the use of a network meta-analysis allows us to mathematically compare different regimens, provided that there is a common comparator (which, in this case was 7 days of standard treatment with PPI, clarithro, and amox or metronidazole


  • 32,056 patients were involved in the efficacy analysis and 22,180 in the treatment tolerance analysis
  • Average age 47, 53% men
  • The real laggards in treatment efficacy (documented elimination of h pylori) were:
    • 7 days of levofloxacin, PPI, and 1 antibiotic
    • 7 days of bismuth, PPI and 2 antibiotics
  • In general, longer treatments did better, though the top rankings were (with the reference being the 7-day standard treatment, which has eradication rate of 0.73 (0.71-0.75):
    • 7 days of PPI, 3 antibiotics (often amox, clarithro, and 5-nitroimidazole) [5-nitroimidazoles include metronidazole and tinidazole, though h pylori sensitivities to these different 5-nitroimidazoles can vary]: eradication rate of 0.94 (0.89-0.98)
    • 10 or 14 days ofPPI and 3 antibiotics (often amox, clarithro, and 5-nitroimidazole): eradication rate of 0.91 (0.87-0.94)
    • 10 or 14 days of PPI, clarithro and (amoxacillin or metronidazole), supplemented by probiotics: eradication rate of 0.90 (0.85-0.94)
    • 10 or 14 days of PPI, levofloxacin, plus 1 antibiotic: eradication rate of 0.90 (0.84-0.94)​
    • 10 or 14 days (sequential) — 5 or 7 days of PPI plus amoxacillin, followed by 5 or 7 days of PPI, clarithro and (5-nitroimidazole or amoxacilin): eradication rate of 0.87 (0.85-0.90)
    • 10 or 14 days of PPI, bismuth compounds, and 2 antibiotics: eradication rate of 0.85 (0.82-0.89)​​
  • Tolerance to therapy
    • In general, the shorter the course of therapy, the better tolerated
    • The best tolerated therapies were:
      • 7 days of the standard 7 days of PPI, clarithromycin and (amoxacillin or metronidazole) along with a probiotic, having a risk of adverse events being 35% lower than the standard 7 day treatment by itself
      • 7 days of PPI, levoflox and 1 antibiotic
      • The rest did not reach statistical significance

So, a few issues:

  • See the array of H pylori articles in prior blogs, including more specific data on some of the more useful regimens (see
  • I did not include the network meta-analysis results using rantidine bismuth citrate, since this does not appear to be available in the US
  • This network meta-analysis is a mathematical tool to try to look for relative rankings of different therapies which were never directly compared, and suffers from several issues. One of the most important is that h. pylori antibiotic sensitivities range dramatically from one country to another (likely based on prevalent use of the antibiotics for other indications in that country, leading to h pylori resistance), and there are studies showing improved h pylori eradication with targeted therapies based on resistance patterns (as noted in​
  • One interesting/paradoxical conclusion from this network meta-analysis is that, as opposed to all other comparisons, the shorter duration of PPI and 3 antibiotics fared better than the 10 or 14 day courses of the same regimen
  • Another striking finding was that the bismuth based regimens did somewhat less well, despite a very strong study (see
  • As a meta-analysis, it is hard to get more specifics (when they give choices, such as amoxacillin or metronidazole, are there any differences between them. Or between the different 5-nitroimidazoles. Or it there a difference by which probiotics were used. Or is there any difference between 10 and 14 days of therapy.) Also, some of what would seem to be the best regimens had very few participants, so the confidence intervals were very large, and they were under-represented in the final analysis. The studies using probiotics were both fewer in number and of poorer design. And, they were unable to control for smoking and alcohol, potential effect modifiers.
  • And, one very important issue in the US is that we do not have data (at least in Boston) on h pylori sensitivities. Maybe that makes sense. One of our greatest assets in Boston is the wonderful ethnic diversity here. One of the problems (at least as h pylori is concerned) is that h pylori organisms from different parts of the world are here​ with their different antibiotic sensitivities. So applying averaged sensitivities may not really benefit the individual patient in front of you.
  • My best guess, from my own experience and reading, is that I use the 10 day sequential therapy (a bit more complicated: 5 days of PPI bid and amoxacillin 1gm bid, followed by 5 days of PPI bid, clarithromycin 500 bid, and metronidazole 500 bid), and in the very few cases of persistent infection (mostly detected by stool antigen testing), I use the bismuth based regimen: high dose PPIbid, amoxicillin 1gm bid, levofloxacin 500 mg in the evening, and bismuth subcitrate 240mg bid for 14 days. So far, so good…. but I should add that the standard 7 day treatment does well in areas where there is clarithromycin resistance rates of <10% (as in the UK). But lacking data in the US, where there are lots of (unnecessary) azithromycin prescriptions (e.g., see ), I suspect that h pylori resistance is pretty high.

Primary Care Corner with Geoffrey Modest MD: DPP-4 Inhibitors in Diabetics and Severe Joint Pain

2 Sep, 15 | by EBM

By. Dr. Geoffrey Modest

The FDA just came out with a warning about DPP-4 inhibitors causing severe joint pain (see ). They reviewed their FDA Adverse Event Reporting System (FAERS) database and the medical literature and identified cases of severe joint pain associated with the use of DPP-4 inhibitors, with symptoms starting 1 day to years after starting the DPP-4 inhibitor, and relief of symptoms usually within a month of stopping the med.


  • They identified 33 such cases, all resulting in “substantial reduction in their prior level of activity”, and 10 of whom were hospitalized
  • In 22 cases, the joint symptoms developed within one month of starting the med
  • In 23, the symptoms resolved within a month of stopping the med
  • 8 had recurrent symptoms on rechallenge with DPP-4 inhibitor (6 of them with a different DPP-4 inhibitor)
  • 10 of the cases suggested an immunological reaction with fever, chills, rash and swelling.
  • 8 of 13 who had immunological testing had normal results, 2 with positive ANA, 1 with increased ESR, 1 with increased CRP, and 1 with antinuclear cytoplasmic antibody (i.e., nonspecific)

As a result, the FDA is adding this “Warning and Precaution” to the drugs.

DPP-4 inhibitors (dipeptidyl peptidase-4 inhibitors, which include sitagliptin, saxagliptin, linagliptin, and alogliptin) are newer agents used in the treatment of diabetes, and data on their efficacy in diabetes is based on their effect on HgbA1C levels (which is pretty minimal at that!!  See blog from June 2015 which notes that A1c improves only a little, and there is no cardiac protection, a primary clinical endpoint​, even after 3 years in almost 15K people with average age of 66). So, from my perspective these meds are expensive and minimally useful adjuncts to therapy at best, and not surprisingly lead to adverse effects (by blocking DPP-4, they effectively block a ubiquitous enzyme on the surface of most cells and deactivate a variety of bioactive peptides).


Primary Care Corner with Geoffrey Modest MD: Chemotherapy at End of Life

1 Sep, 15 | by EBM

By Dr. Geoffrey Modest

A recent multi-institutional longitudinal cohort study assessed the use of chemotherapy in patients with progressive metastatic cancer, assessing survival, quality of life (QOL), and the relationship to performance status (see doi:10.1001/jamaoncol.2015.2378).


  • The American Society of Clinical Oncology (ASCO) in 2012 published a list of their “Choosing-Wisely” 5 opportunities to improve care and decrease costs, noting that chemotherapy use among patients with no evidence of clinical benefit was the most wasteful, unnecessary and widespread practice in oncology, especially in those with poor performance status with an Eastern Cooperative Oncology Group (ECOG) score of 3 or more (“capable of only limited self-care, confined to bed or chair >50% of waking hours”). Older studies from the 1980s have confirmed that those with poor performance had low response rates to chemotherapy, high rates of toxic effects, and shorter survival.
  • But, despite lack of evidence to support the practice, a paper in 2012 found that 40% of patients with non-small cell lung cancer and  ECOG score of 3-4 received palliative chemotherapy, with almost no hope of benefit. A Norwegian study also found that 53% of patients with ECOG performance score of 2 (in bed <50% of time)and 16% with scores of 3-4 received palliative chemotherapy, with 10% having chemotherapy in the last 30 days of their lives.


  • 312 patients were reviewed with a diagnosis of end-stage metastatic cancer,  refractory to at least 1 line of chemotherapy and MD-estimated life expectancy of <6 months. 158 received chemotherapy and 154 did not.
  • 8% male, average age 58.6, 12.4 years of education, 61.5% white/20.5% black/16.7% Hispanic.
  • The baseline performance status was assessed on average 3.8 months before death: 122 patients had ECOG score of 1 (somewhat restricted in strenuous physical activities but ambulatory), 116 with score of 2 , 58 with score of 3


  • On multiple logistic regression, those receiving chemotherapy were much more likely to be in an academic medical center than community clinic (adjusted odds ratio of 17.1, with the vast majority receiving chemotherapy at the academic centers at Yale, Simmons in Dallas, and Dana-Farber in Boston; about 50/50 at the West Haven VA and Parkland; and a significant minority in New Hampshire Oncology-Hematology); had better ECOG performance scores (AOR=0.67); had pancreatic (AOR= 4.07) and breast cancer (AOR=2.45); and were younger (AOR=0.96)
  • Patients’ risk of death was NOT significantly associated with whether they received chemotherapy or not, after adjusting for enrollment site and baseline ECOG score
  • In assessing QOD (QOL near death, asking the caregiver most knowledgeable about the health care of the patient in his/her final week of life by a validated questionnaire), by performance status:
    • ECOG 1: lower QOD !!! [odds ratio 0.35 (0.17-0.75), p=0.01]
    • ECOG 2: QOD [relative risk 1.06 (0.51-2.21), p=0.87, NS]
    • ECOG 3: QOD [relative risk 1.34 (0.46-3.89), p=0.59, NS]

So, a few issues:

  • This was a retrospective analysis of a cohort study and is therefore limited by not having individual data on the people who had chemotherapy vs not. Also there was likely a significant selection bias in those choosing a prestigious academic medical center vs a community-based center for their care.
  • But, it is still quite striking that of those in the academic medical centers 79% had chemotherapy, vs 46% at the VA and 22% in the community-based practice.
  • One of the most useful findings was that despite no difference in survival (again, not the most conclusive data, given limitations of study design/data), those with the best performance scores as assessed by their closest caregivers​​ <4 months prior to death actually had much worse QOL when given chemotherapy.
  • A related issue, I have some concern about palliative care being a separate discipline from oncology. Although I assume that oncologists in general do get significant training in end-of-life management, I have heard examples of oncologists just referring patients to palliative care specialists to discuss these issues. To the extent that there is a separation, this creates the unfortunate dynamic of oncologists pushing therapies, even not terribly beneficial ones, on the one side, and the palliative care specialists pushing for a more rational discussion of the benefits and risks of therapy (which they may not understand fully, given lack of oncology training in many cases). Without an integrated, coherent approach, the patient is caught in the middle, perhaps being emotionally swayed by the thought that there is a potential therapy. In addition, oncologists historically have had a significant financial interest in giving meds. There was a major rollback of the huge profit margin oncologists had received prior to 2005 for administering medications they bought and administered. Now there is a 6% markup of the Average Sales Price, though Congress realized that this would dramatically decrease oncologist income, so they significantly increased the fees paid for chemotherapy administration. Coincident with this reimbursement change, “physicians switched from dispensing the drugs that experienced the largest cuts in profitability… to other high-margin drugs” –see Health Affairs July 2010; 29: 1391-9.  And the office-based administration fees skyrocketed in some cases (I suspect more so in the large cancer centers). So there still is a significant financial incentive for many oncologists to give drugs… and the concern is that this financial incentive, especially if the oncologist is not so involved in the individual’s end-of-life/palliative care issues, could lead to inappropriate/unnecessary, potentially harmful, and expensive care.

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