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Archive for February, 2016

Primary Care Corner with Geoffrey Modest MD: H Pylori Eradication and Reduced Risk of Gastric Cancer

29 Feb, 16 | by EBM

By Dr. Geoffrey Modest

A recent systematic review/meta-analysis looked at the effects of H pylori eradication and the incidence of gastric cancer (see ​


  • Background:
  • There are >720,000 deaths/yr from gastric cancer worldwide
  • H pylori infection is the most important etiologic factor, infecting approximately 50% of the global population, and estimated to cause 78% of gastric cancers
  • ​Mechanistically, H pylori causes chronic gastric inflammation, leading to precancerous changes of atrophic gastritis, and also to gastric mucosal genetic instability through decreased acid secretion, “which can promote the growth of gastric microbiome that processes dietary components into carcinogens”
  • ​24 studies, with a total of 715 incident gastric cancers among a total of 48,064 patients and 340,255 person-years of follow-up. Almost all of the studies were from Korea, China and Japan. 14 studies were in asymptomatic individuals and 10 were in those who had undergone endoscopic resection of early gastric cancers


  • 253 gastric cancers developed in 20,484 individuals who received H pylori treatment and 462 of 27,580 who did not get the treatment
  • ​Baseline incidence of gastric cancer in those not getting treatment varied widely from 34.3 to 10,265.4/100K person-years
  • ​Those with H pylori eradication had 46% lower incidence of gastric cancer (pooled incidence rate ratio of 0.54 (0.46-0.65), with little heterogeneity among the studies
  • Eradication of H pylori in asymptomatic individuals still had significant benefit (pooled incidence rate ratio of 0.62 (0.49-0.79)
  • The benefit of eradication in the group with endoscopic gastric cancer resection was even better, with pooled incidence rate ratio of 0.46 (0.35-0.60)
  • ​The benefit of eradication was (not surprisingly) more significant in areas with a high baseline rate of gastric cancer (if 2,970 to 10,256.4/100K person-years​, then pooled incidence rate ratios were 0.45); decreased in those with intermediate rates (314.3-2914.2/100K person-years, pooled incidence rate ratios were 0.49; and was not significant if low rates (34.2-253.6/100K person-years, ​ pooled incidence rate ratios were 0.80)


  • In another study by the current authors, a population-based mass eradication program on Matsu Island of Taiwan, found that H pylori eradication reduced atrophic gastritis in patients with premalignant lesions and reduced cancer incidence by 25% (from 40.3 to 30.4/100K person-years)
  • Unlike some other studies, the systematic review above found that even treating those with early gastric cancers had some benefit
  • I am a little concerned about generalizing these results to other areas of the world, since these studies are mostly from Asia, and more developed regions of Asia at that. For example, in many countries with high rates of H pylori, there are not the epidemiologic data on the real incidence/prevalence of either H pylori or gastric cancer. I am also not sure that the strains/variants of H pylori are the same in different regions, or even have the same association with gastric cancer. That being said, I spoke with a public health-minded physician from Cape Verde, an area where many of our patients come from, and he was under the impression that there was a lot of gastric cancer there. But there are no concrete data, and the prevalence could well vary from island to island. I did decide to test and treat my patients after I found a few cases of gastric cancer in Capeverdean patients (long live anecdotes ….​)
  • I have sent out many blogs on H pylori in the past, since it is such a big issue in much of the world and so prevalent in many of the immigrant communities in the US. See: which comments on endoscopic screening for high risk patients (again, in Korea, Japan, and China) for an array of articles on H pylori regimens (including salvage regimens) and one on the increased risk of GI bleeding in patients with H pylori and taking NSAIDs


Primary Care Corner with Geoffrey Modest MD: Adult Depression Guidelines

26 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The American College of Physicians released a clinical practice guideline on nonpharmacologic vs pharmacologic treatment of adults with major depressive disorder–MDD (see file:///C:/Users/geoff/Downloads/AIME201603010-M152570.pdf ).



  • MDD, defined as in DSM-V: depressed mood or loss of pleasure or interest, along with other symptoms (changes in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation nearly every day, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, indecisiveness or decreased ability to concentrate, and recurrent thoughts of death or suicide), lasting at least 2 weeks and affecting normal functioning
  • MDD has estimated lifetime prevalence of 16% in the US
  • 8 million ambulatory visits/year
  • Estimated economic cost to society and health care in 2000 was $83.1 billion (and probably higher today)
  • Definition of treatment response: a decrease of at least 50% in one of the tools [Patient Health Questionnaire-9 (PHQ-9) or Hamilton Depression Rating Scale (HAM-D); for meds, they only looked at second-generation antidepressants (i.e., not tricyclics, MAO inhibitors, which, by the way, are probably as effective in a few trials, but have more adverse effects and discontinuations); they also assessed nonpharmacologic approaches: psychological (acceptance and commitment therapy, cognitive behavioral therapy CBT, interpersonal therapy, psychodynamic therapy), complementary and alternative medicine (CAM) approaches (acupuncture, meditation, w-3 fatty acids, S-adenosly-L-methionine SAMe, St John’s wort, and yoga) and exercise


  • ​Meds vs CBT: no difference in outcome comparing the two after 8-52 weeks of treatment, for remission rates or functional capacity (mod quality evidence, 5 trials); 2 trials did not find benefit from combo therapy for remission after 12-52 weeks of therapy (low-quality evidence​)​, though perhaps some benefit in functional capacity.
  • Meds vs interpersonal therapy: no difference in response (3 trials, low-quality evidence​); no real evidence of combo therapy (only 1 low-quality trial which used nefazodone as the med).
  • Meds vs psychodynamic therapies: no difference for remission or functional capacity (3 trials, low-quality evidence).
  • Meds vs acupuncture: no diff comparing fluoxetine vs acupuncture after 6 weeks (1 trial, low-quality evidence​); combo fluoxetine or paroxetine with acupuncture found improved response after 6 weeks (2 trials, low-quality evidence​)
  • Meds vs w-3 fatty acids: meds better than w-3 fatty acids (1 trial, low-quality evidence​)
  • Meds vs SAMe: no diff in study with escitalopram (1 trial, low-quality evidence​)
  • Meds vs St John’s wort: no diff from 9 trials (low-quality evidence ​because meds not used at usual therapeutic dosage range. Other issues include non-regulation of St John’s wort by FDA and variable potency, important drug-drug interactions by inducing cytochrome P450 isoenzyme 3A4)
  • Meds vs yoga: no trials done
  • Meds vs exercise: no diff in response, including 2 trials with moderate quality of evidence for sertraline vs exercise after 16 weeks
  • ​Switching meds: no difference in response rate by switching from one med to another. Mod quality evidence [but very few studies evaluated: switching from bupropion vs sertraline or venlafaxine and sertraline vs venlafaxine], no diff in adverse events/discontinuation rates
  • Switching from med to different med vs switching to CBT: no difference, but 1 study with low-quality evidence
  • Augmenting one med with another: no difference in augmenting citalopram with bupropion vs buspirone (though adding bupropion decreased depression severity more than buspirone (1 trial with low-quality evidence)
  • Augmenting med with another vs augmenting with CBT: no difference in response, remission, depression severity if augment citalopram with buspirone or bupropion vs augmenting with CBT
  • ​In terms of harms overall: pretty mixed. Some trials with more discontinuation with meds vs psych therapies. Not much difference with (though acupuncture and St John’s wort did have fewer adverse events than meds)

Their conclusion: offer either CBT or med for patients with MDD after discussion treatment and adverse effects (strong recommendation; moderate quality evidence)

So, I’m not sure what to make of this. It is pretty clear that the studies evaluated did not create a basis for strong recommendations: in general only very few studies were included (reflecting the paucity of strict RCTs) and the majority had low-quality evidence. And several common management strategies were dismissed because of no formal studies being done (e.g., using the same med to retreat a person with depression who had previously responded to that med).

A few points:

  • There are several other common treatment strategies that were dismissed for lack of higher quality evidence, where in fact there are some supportive data:
    • Switching from one med to another when the first one does not work. I have seen a few studies (though do not have the reference handy) finding that switching SSRIs from one to another in nonresponders increases the response rate from a baseline group response rate to about 15-20% higher with a different SSRI. And, my clinical practice of trying one and, if no response, switching to another has been reasonably effective. If there is a partial response to the initial SSRI, I typically try either increasing the dose or augmentation (as in next point).
    • Adding an augmenting med to an antidepressant when there is suboptimal initial response. Again, the data are not great, and a systematic review overall did not find benefit for augmentation (though 2 or the 5 RCTs did). On the other hand, an impressive and pretty large trial (not a clean RCT) of patients with suboptimal response to citalopram did find benefit for augmentation with either bupropion or buspirone (somewhat better with bupropion) – see NEJM 2006; 354: 1243. And my personal experience pretty strongly supports augmentation with bupropion in those with partial responses to an SSRI.
    • Combining a med with psychotherapy. Several studies have confirmed an augmented effect of using this combined approach: e.g. World Psychiatry 2014; 13: 56 — a large meta-analysis of patients with MDD finding a clinically meaningful effect of combination therapy over meds alone.
  • Perhaps the biggest issue with these guidelines is the limitation of randomized controlled trials (RCTs) themselves, in terms of their generalizability to the patient sitting in front of you:
    • Structural issues: the RCT patients may be predominantly of a different gender, ethnicity, or have different comorbidities than your patient (and even in the best large RCTs with representation of many different types of people, any subgroup analysis looking at the factors most reflective of the patient you are treating are typically post-hoc analyses, which limit their statistical validity by introducing potential biases)
    • ​Exclusion criteria: RCTs have upfront exclusions which make the study data cleaner and easier to analyze; e.g. patients with cancer or renal failure, etc. are excluded (because of limited life expectancy, confounders with meds taken, other medical issues, etc.). But we still need to treat patients with these conditions…. Does the RCT really apply to them?
    • Inclusion criteria: a study may well find that meds vs psychotherapy are equivalent. But in order to be part of the study, those patients recruited must agree to be randomly assigned to either wing of the study, prior to randomization. but many patients (at least many of mine) are not good candidates for psychotherapy (not willing to go, too little insight for therapy to be useful, etc.), so there is a selection bias in terms of who participates in the RCT, and there may be real differences between those patients who would participate in a study and those who would not (i.e., their depression in the setting of who they are may respond differently to meds, for example).
  • Real-world applicability of RCT results: primary care providers do not have accessible study nurses who call the patients regularly, see if there are any problems, make sure they are taking their meds and perhaps do pill counts, make sure they make it to their psychotherapy appointments/etc., and have the drug company sponsors pay for all of the copays, transportation costs, and give the patient financial incentives to adhere to the protocol. Our real world patients may have little of these benefits, and may respond to treatments differently than the study patients as a result.
  • Placebo effect: an assumption in RCTs is that they are trying to prove that there is an incremental value of a new med, for example, over placebo. But maybe the placebo effect is clinically important???  There may be no trial showing that choosing a med based on either the patient’s prior success or that of a family member leads to a higher likelihood of success in the patient in front of you. BUT, first of all, there may be lack of recommendations about this just because the study was never done (i.e., there actually may be a benefit in choosing an SSRI based on this, we just don’t know). AND, even if there is a placebo effect, such that there is an increased response if the med worked before or in a family member, that’s clinically important and in the patient’s interest…..
  • So, this is not to say that there is no real use or even real importance of RCTs, just that there are limitations to their generalizability. And in the above case of depression, both the lack of studies to answer important questions and the assumption that we need to minimize the placebo affect should not necessarily undercut the applicability of treatments. Perhaps the main points of the guidelines are that there is reasonable equivalence overall to meds and psychotherapy (esp. CBT) overall, but that for such a really common problem as MDD, there are embarrassingly few high quality studies addressing the pressing clinical issues we see day-in and day-out…

Primary Care Corner with Geoffrey Modest MD: PPI Use and Dementia

25 Feb, 16 | by EBM

By Dr. Geoffrey Modest

A ​pharmacoepidemiological analysis, based on claims data, found an association between taking proton pump inhibitors (PPIs) and the risk of dementia in the elderly (see doi:10.1001/jamaneurol.2015.4791).


  • An observational database from 2004-2011 from the largest Germany health insurer insuring 1/3 of the population and 50% of the elderly, was used to assess inpatient and outpatient use of PPIs
  • 73679 participants, >=75yo and free of dementia at baseline. 2950 were on regular PPIs (mean age 83.8, 78% female), compared to 70,729 patients (mean age 83.0, 73.6% female)
  • 29510 patients received a diagnosis of dementia over the course of the study period (40% of the cohort)
  • Regular PPI use was defined as a prescription for a PPI each quarter of an 18-month interval during the study period


  • Those on PPIs had a 44% increased risk of incident dementia [HR 1.44 (1.36-1.52), p<0.001]
    • For males, HR 1.52 (1.33-1.74)
    • For females, HR 1.42 (1.33-1.51)
  • Other associations with dementia included: depression (HR 1.28), stroke (HR 1.37), and to a lesser extent, female sex (HR 1.15), diabetes (HR 1.05), polypharmacy (HR 1.16); all statistically significant
  • ​But, controlling for all these potentially confounding factors actually led to a higher association of dementia with PPI use [HR 1.66 (1.57-1.76)]
  • And, controlling for use of anticholinergics, itself a risk factor for dementia with its own HR of 1.80, did not change the association with PPIs (HR was still 1.44)
  • Looking at those patients who only occasionally used PPIs, there was a lower but significant HR of 1.16 (1.13-1.19).
  • Difference by type of PPI used: omeprazole had HR 1.51, pantoprazole HR 1.58, but somewhat higher with esomeprazole with HR 2.12
  • ​There was a slight decreasing effect with age: those 75-79 had HR 1.69, those 80-84 had HR 1.49 and those >84 had HR 1.32 (all significant)

A prior study by the same group, AgeCoDe (the German Study on Aging, Cognition and Dementia in Primary Care Patients), included 3327 community-dwelling persons >= 75 yo with 18-month neuropsychological assessments similarly found incident dementia to be associated with PPI usage, and with a similar HR of 1.38 (1.04-1.83), and with somewhat more dementia in the group on esomeprazole. All PPI associations controlled for age, sex, educational level, apoE4, depression, diabetes, stroke, ischemic heart disease, and polypharmacy.

So, this was a large computer-based study finding an association between PPI use and dementia; therefore it is not confirm a causal relationship. But a few points:

  • There is biological plausibility:
    • Mouse models find that PPIs increase the levels of b-amyloid in their brains, by affecting the enzymes b- and g-secretase; PPIs also could decrease the degradation of b-amyloid by lysosomes, which are pH-dependent, in microglia (and some PPIs cross the blood-brain barrier). Also, PPIs bind to tau.
    • PPIs are associated with vitamin B12 deficiency through malabsorption, and vitamin B12 deficiency is associated with cognitive decline
  • This study adds to the potential adverse effects of PPIs (see blogs below for some other problems with PPIs)
  • Of course, this study only finds an association. As above, they tried to account for many of the covariates for dementia (stroke, polypharmacy, depression, etc.), and they also found that there was not much difference in use of the health care system (all suggesting, but not proving, that the PPI-users and non-users were pretty similar in dementia risk). But the data are not so granular: i.e., even if the level of polypharmacy is the same in both groups, did those on PPIs might have more specific drugs that could affect cognition? And what about cigarette use, alcohol, or obesity which may be over-represented in the PPI-user group and may themselves be associated with dementia?
  • So, I think there are a couple of lessons here:
    • It is always important to remember that very few drugs really are targeted specifically to a single action. One might think (as perhaps most of us did) that a drug targeting acid release from the stomach’s parietal cells would not have potential widespread effects (other than collateral damage on nutrient absorption, etc.). The finding of clear effects on b-amyloid in mice brains and the potential effects of PPIs on human brains yet again brings us to the usual conclusion: use medications in their lowest dose and only if necessary, with an emphasis on helping patients try to make lifestyle changes as the primary approach to many medical problems.
    • As mentioned in prior blogs, it is really easy to just keep refilling PPI prescriptions since they work and it is sometimes a struggle to change paths with patients, and we often are quite busy just keeping up with the other more active medical problems. I.e., the approach of step-down therapy (moving from PPI to H2-blocker or just calcium) is in reality not done much in clinical practice. Which I think supports more of a step-up approach (staring with calcium then escalating to H2 blocker prior to PPI).

For a few of the recent blogs on PPIs, see which looks at microbiome changes with gastric acid suppression which looks at the possible association of PPIs with MIs found an association of PPIs with chronic kidney disease

Primary Care Corner with Geoffrey Modest MD: Increasing Disparities in Life Expectancy

24 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The NY Times just featured an article on the growing longevity disparity associated with income disparity (see ), based on a report released by the Brookings Institute. See for a brief review of the report and for the full 174 page report.

Main points:

  • In the early 1970s, a 60-year old man in the top half of the earnings’ ladder had life expectancy 1.2 years longer than one in the bottom half. In 2001, the gap was 5.8 years.
  • The Brookings report found that, comparing life expectancy between those in the top vs bottom 10% of earners (data are based on life expectancy at age 50 yo):
    • For men born in 1920, there was a 6-year difference; for men born in 1950, there was a 14-year difference.
    • For women born in 1920, there was a 4.7-year difference; for women born in 1950, there was a 13-year difference.
    • In a separate analysis, the Brookings report noted that life expectancies in those born in 1920 vs 1940, comparing the bottom to the top 10% of mid-career income distribution were:
      • Those in the bottom 10%: 80.4 years for women (no change); 74.3 increasing to 76.0 in men
      • Those in the top 10%: 84.1 years for women increasing to 90.5!!!; 79.3 increasing to 88.0!!! In men
    • Why are the differences so great and getting dramatically greater? Hard to pinpoint exactly (and studies looked at different endpoints), but some differences:
      • Cigarette smoking: decreased more in wealthy, could explain 1/5 to 1/3 in the gap between men with college degrees vs those with high school degrees; 1/4 of the gap in women
      • Obesity: rates of obesity between rich and poor narrowed from 1990-2010, when 37% of poorer and 31% of richer adults were obese
      • ​Prescription drug abuse has disproportionately increased mortality in poor communities
      • Of note, limited access to care was not found to play much of a role (they reference an article by Steven Schroeder: N Engl J Med 2007; 357:1221), stating that only 10% of the disparity has to do with medical care [note that this statement was not footnoted, so I cannot check on the reliability of it].
    • One side note is that wealthier people live longer and therefore collect more years of social security payments as well as longer utilization of Medicare services, disproportionate financial benefits for the wealthy.
    • These longevity disparities are not necessarily reflected in other countries: in Canada, men in the poorest urban areas had the largest declines in heart disease mortality from 1971-1996, and the overall gaps in longevity decreased over this time period. Cancer survival rates in low-income residents in Toronto were significantly better than in Detroit, yet there was no difference for middle- and high-income residents (see Am J Public Health. 1997; 87(7): 1156).
    • The Brookings report also commented on the fact that higher wage earners are retiring later (they attribute this to the fact that their jobs are higher-paying which is especially important since most jobs now do not come with a pension or guaranteed income after retirement, the jobs usually are more rewarding, and social security benefits were pushed up a year to age 66). Lower age workers tend to retire earlier with only 13.8% getting social security at age 66. They do not comment explicitly (so, I will): the increase in age for social security from 65 to 66 is much less significant for an office worker than someone doing hard manual labor, where they likely have chronic musculoskeletal pains/problems, and the possibility of extending the work-life another year may be painful and undoable. But getting social security early adds to income inequality, since the payout is much less/yr.


In a (somewhat) related recent article (see JAMA. 2016;315(6):609), researchers looked at life expectancy from birth (vs from age 50 in above), as a means to evaluate mortality in younger people, where both the major causes of death are different from those >50yo (more from injury/trauma/drugs), and the impact is greater (more years of expected life are lost). They focused on motor vehicle traffic crashes (MVT), firearm injuries, and drug poisonings (e.g. overdoses). The table below shows the contribution of these injuries/traumas to the life expectancy of men and women, also comparing the US rates to those of a variety of other countries. From this data, overall death from injury accounted for 48% of the longevity gap in men (1.02 years of the 2.15 years of the all-cause difference), with firearm-related injuries accounting for 21% of the overall gap, drug poisonings 14% and MVT crashes 13%. For women injuries/traumas accounted for 19% of the gap, with 4% from firearms, 9% from drug poisonings, and 6% from MVT crashes. Overall, the impact of these injuries in the US is far greater than in a combination of other countries. The other table (not shown) details the specifics per country, showing for example that although Portugal is the only country in the list with an overall death rate higher than the US, their death rate from injuries is much lower than the US, so that Portugal still has a life-expectancy 0.5 years longer than the US (i.e., because there are fewer injuries/overdoses which disproportionately affect younger people). A caveat here is that they are relying on death coding across different countries.

A few comments:

  • There are very real reasons why lower wage earners have lower life expectancy, as noted in many prior blogs. Obesity is a major problem but is exacerbated by lack of access to good, affordable foods. Doing exercise can be an obstacle when people live in unsafe neighborhoods. Manual laborers tend to have more disabilities (I’m not sure I have met any construction workers, masons, plumbers, who do not have significant musculoskeletal problems by the age of 40). Air quality tends to be worse in poor neighborhoods. General stress tends to be higher.
  • I do have concerns about writing off access to medical care as not much of a factor in the longevity discrepancy. It is clear that inadequate access to care is an issue for the poor only. And there are huge discrepancies within that group. If you happen to live in Massachusetts, access is generally quite good. If you live in rural Mississippi or Louisiana, access is terrible/can be effectively nonexistent.
  • Though I do think that, overall, the predominant issue is that, though we spend lots of $$ in the US on health care, unlike other countries (including many with far fewer resources than in the US), we spend the vast majority on “medical care” (where in other countries a higher % of health care money goes to making sure people have good food, housing, jobs, and an array of social services –see The American Health Care Paradox, by E Bradley and L Taylor, published in 2013, noting that:
    • We spend almost twice as much money as the next most expensive health care system; yet we have really terrible comparable health outcomes, e.g. ranking 26th in life expectancy.
    • ​Countries with far better health outcomes spend much more money on social services to enhance well-being, such as “investments in housing, nutrition, education, the environment and unemployment support” (which dovetails with the way the World Health Organization defines health as “a state of complete physical, mental and social well-being”); we spend dramatically less than other countries on these social services.
    • ​And, if you add up the strictly medical as well as the social costs invested by different countries for health care, the US is somewhere in the middle of the pack in terms of per capita spending.
  • So,  I think this is why longevity of wealthier people in the US (who need fewer social services) is pretty much as good at those living in the highest ranking countries (Japan, Iceland), but poorer people have the life expectancy of those in Poland and the Czech republic.
  • There are several reports finding a temporal relationship between divergences in income inequality and longevity inequality over the past 40 years.
  • And the JAMA study reinforces the overall importance of traumatic or drug-related deaths overall (which is largely missed in the Brookings analysis), and especially in the young​.

Primary Care Corner with Geoffrey Modest MD: Crohn’s Disease – Should We Recommend Eating Fiber?

23 Feb, 16 | by EBM

By Dr. Geoffrey Modest

In an observational study, researchers found that there was a decrease in Crohn’s disease flares in those on higher fiber diets (see​).


  • 1619 patients in the Crohn’s and Colitis Foundation of America Partners Internet cohort (an online database of more than 14,000 people with inflammatory bowel disease, IBD) completed a 26-item dietary survey. The study was limited to those in remission at baseline, with a follow-up survey 6 months later
  • 1130 patients had Crohn’s disease– CD (30% male, 46% had surgery, 53% had disease >10 years, mean fiber intake 16 g/d, 22% with flare at follow-up assessment, 6% on steroids, 65% on immunosuppressants, 69% on aminosalicylates and 68% on biologicals), and 489 had ulcerative colitis — UC (31% male, 4% had surgery, 43% had disease >10 years, mean fiber intake 18 g/d, 28% with flare at follow-up assessment, 5% on steroids, 64% on immunosuppressants, 85% on aminosalicylates and 55% on biologicals)


  • Those with ulcerative colitis were 2.6x more likely to be in the upper quartile of fiber intake, vs those with Crohn’s: OR 2.63 (1.91-3.62). The mean fiber intake in the upper quartile of those with Crohn’s was 23.7 g/d, and with ulcerative colitis was 24.5 g/d.
  • ​Men were about 5x more likely than women to be high fiber consumers: OR 4.74 (3.34-6.73)
  • Crohn’s disease
    • Comparing those on the highest to lowest fiber intake quartile, OR for having flare was 0.58 (0.37-0.90), a 42% decrease
    • Comparing the top decile to the bottom one: here was an even more pronounced effect size: OR 0.37 (0.16-0.85), or a 63% decrease
    • ​Overall results were similar if looking at whole grain consumption as part of the fiber
  • Ulcerative Colitis
    • ​No association between fiber intake and flares of UC
    • ​Though if look at the top vs the bottom decile of fiber consumption, there was a significant increase in flares with OR 4.78 (1.05-21.66) in those consuming more fiber [note the wide confidence intervals, which may reflect the smaller numbers of patients, making the point estimates unreliable; also, of unclear significance, those with UC tended to eat more fiber overall than those with CD]

So, a few issues:

  • Inflammatory bowel disease is associated with an abnormal mucosal immune response to commensal bacteria in the gut. And several studies in people without IBD have found that a high dietary fiber intake changes the gut microbiome, increasing short-chain fatty acids and butyrate production (butyrate has the positive effect of inhibiting inflammation, carcinogenesis and oxidative stress in the gut), which could conceivably help people with IBD (see for some prior blogs on the microbiome)
  • But, though the data on fiber’s role has never been very clear, it is frequent that patients with IBD are told to limit their dietary intake of fiber [though, interesting in this study that those with CD reported eating a mean of 16 g/d, those with ulcerative colitis 18g/d, and these are pretty much the same as in the general population of 17 g/d per the National Health and Nutrition Examination Survey of 2009-10]. My understanding is that many people are afraid of the high fiber diet bulk in patients with CD and strictures, and that different patients are pretty different in what diets work best for them. There are several epidemiological studies, however, suggesting that a high fiber diet is helpful in preventing the development of CD.
  • It was also notable that the trend in UC was to more flares in those on higher fiber diets; and when looking at deciles of fiber intake, the increase was actually statistically significant. The concern in UC about fiber in some ways is less than with CD, since there are fewer strictures. Yet those with UC ate more fiber and had a higher propensity to flares.
  • This study was nonrandomized, creating significant room for bias. For example, maybe those people who elected to have a higher fiber diet were different from those who chose a low fiber diet? Maybe they had less severe disease in some ways than those having lower fiber intake (e.g., maybe those on a lower fiber diet had worse disease, more strictures and were afraid of obstruction): so perhaps there was a preselection bias of those with less bad disease eating more fiber?? The researchers did note that those on lower fiber diet tended to have longer duration of disease, past history of surgery, or past hospitalization for IBD, which suggests that there may have been a bias.
  • There was a systematic review of the role of fiber in patients with IBD (see Inflamm Bowel Dis. 2014 Mar;20(3):576), which assessed 23 RCTs (10 with CD and 12 with UC) and 1296 patients, finding that in UC 3/10 studies supported fiber supplementation but 0/12 in those with CD, though several studies did find improvement in GI symptoms and favorable changes in the microbiome with fiber. Although they were not specific clinical endpoints in the studies designs, several studies also found improvements in disease activity within the fiber group. Notably, there was no negative effect of high fiber diet in those with acute disease, either with UC or CD, and one showed positive effect in those with UC. Of note, these studies were so different in design that they could not do a meta-analysis.
  • So, given the potentially positive effects of a higher fiber diet (positive changes in microbiome, perhaps fewer flares), and in light of the systematic review not finding harm and perhaps some benefit of a higher fiber diet, it might be reasonable to try it. And, as noted above, there does seem to be a lot of individual variation in response to different diets, so any changes should be done with careful follow-up. But, this systematic review, contrary to much of the prevailing wisdom, did support higher fiber diets even during flares (i.e., no negative effects and some positive in those with UC). And it would be great to have a well-conducted, large RCT to really answer the question.
  • The reason I reviewed this study is that I manage a few patients with IBD, the dietary suggestions for IBD had mostly been against a higher fiber diet during flares, and the microbiome changes of high fiber diet seem so positive. I would still be hesitant to recommend this in a patient with CD and strictures, for fear that the combination of increased bowel wall inflammation and increased dietary bulk might not be so great. And some patients may feel worse (there can be more gas and potentially uncomfortable colonic distention with high fiber). But it may be worth a try.

Primary Care Corner with Geoffrey Modest MD: Access to Generic Drug Prices?

22 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The NY Times had an article on a couple of startups which have been able to find and post generic drug prices on the internet (see​ ).


  • Most pharmacies do not list their drug prices, these prices can vary, the cost of meds is really different for insurance companies vs individuals (and the actual price negotiated by health insurers is “proprietary” and not accessible to us mere mortals)
  • Ironically, the out-of-pocket cost for people without insurance can be extraordinarily high as compared to what insurers pay, similar to what happens with lab tests, hospitalizations, etc., since the big players can negotiate lower costs. Which leaves many more impoverished folks paying much higher costs for needed drugs, tests, hospitalizations…
  • And, many consumers cannot even find out their costs till the purchase is rung-up on the cash register
  • Perhaps the only good thing about sleazy drug companies making the news (e.g. Turing and its former malevolent leader Martin Shkreli) is that it brought the issue of usurious pricing/gouging into the public arena. See for more info.
  • There are a couple of new websites devoted to the issue of price transparency, including GoodRx, which publishes prices and accesses available coupons to help pay for drugs. And Blink Health, which allows people to pay online and pick up their drugs at a local pharmacy.
  • A person from a national consulting firm found that the Blink Health prices were comparable to the prices he was able to negotiate for large employers: “it’s about as good as you’d see it”.
  • As an example, a 30-d supply of atorvastatin costs $196 at KMart, $61 at Kroger, and is $12 with a coupon from GoodRx. Blink Health has it for $9.94.
  • GoodRx and Blink Health get their prices from networks of pharmacy-benefit managers. Blink Health entered agreement with MedImpact and relies on their network of >60K pharmacies

So, I tried the website ( and it is: really easy to use, immediately gives a price, has a list of local pharmacies after I typed in my zipcode (including cvs, walgreens, and many others), allows for easy online payment, allows one to cancel the order anytime until it is picked up, has no additional cost when you go to the pharmacy (just what one pays to blink health), and works without any health insurance coverage (I have not really used this website, but the prices for some meds seem to be less than the copays for some insurances. So, this website should really useful for patients who either have very high copays or no insurance….)

  • Not much discount when the med is one of the 10% prescribed in the US which is not generic
  • Pretty shocking that until now there has been so little transparency in the drug market. Are hospitals, labs, etc. to follow??

Primary Care Corner with Geoffrey Modest MD: Stopping Therapy in Chronic Hep B Review

19 Feb, 16 | by EBM

By Dr. Geoffrey Modest

There was a systematic review of discontinuation of antivirals in patients with chronic hepatitis B infection (see 10.1002/hep.28438).


  • 25 studies were reviewed, with 1716 patients
  • Patients with hepatitis B e Antigen (HBeAg-positive) had a durable virologic remission (VR) at 12, 24, and 36 months of 62.5%, 53.4% and 51.5%; no difference if VR defined as HBV DNA <200, <2,000, or <20,000 IU/ml
  • Patients without hepatitis B e Antigen (HBeAg-negative) had a durable virologic remission at 12, 24, and 36 months of 43.7%, 31.3% and 30.1%; those with VR on therapy >24 months vs <24 months had remission in 75.0% vs 35.6%, p=0.005.
  • The probability of a durable VR in patients who were initially HBeAg-positive was not associated with the duration of on-therapy VR (remaining in the 90% range after stopping the antiviral med)—i.e., these response rates were achieved in patients on meds who had HBeAg conversion and undetectable HBV viral loads followed by >=6 months of consolidation therapy in all the studies they found
  • Overall, the likelihood for a durable biochemical remission (no increased ALT, etc.) was about 20% higher than that of a durable viral remission, independent of whether the person was HBeAg positive or negative.​
  • There are limited data on stopping meds in patients with pre-existing cirrhosis [and liver decompensation developed in 2 of 243 patients with cirrhosis (0.8%), jaundice in 6 (2.5%). retreatment was effective in all but one patient, who died of liver failure]
  • The weighted probability of becoming surface antigen negative (HBsAg loss) was 2.0%

So, a few points.

  • There are much better treatments for chronic hepatitis B than before, both for suppression of detectable viral loads and for lack of development of viral resistance. My experience with both entecavir and tenofovir has confirmed sustained viral suppression (and, I hope that the new formulation of tenofovir, tenofovir alafenamide, will be available soon as a solo agent, since it has much less renal or bone toxicities)
  • Data are pretty consistent that using these drugs leads to improvement in liver fibrosis and can reverse cirrhosis (perhaps the most remarkable patient I’ve seen was an older Vietnamese woman with end-stage cirrhosis/portal hypertension/ascites who was discharged from the GI clinic 18 years ago to go back to Vietnam to die. The first article on 3TC (lamivudine) efficacy had just been released in NEJM (see N Engl J Med 1998; 339:61), so I decided to try it, since there seemed to be no downside. remarkably, her ascites resolved completely within a couple of months. And she lived another 5 years in Vietnam. Pretty astounding….
  • Treating patients who are HBeAg positive is easier: they have a definable endpoint (becoming HBeAg negative/HBeAb positive) and seem to respond better to therapy, as confirmed in this systematic review
  • Those who are HBeAg-negative are more complicated, and typically have been relegated to life-long therapy. There have been some small, intriguing studies looking at this group. I sent an email/blog on this in 2012 (see org/10.1053/j.gastro.2012.05.039), prior to the BMJ blog webpage, where 33 patients who were HBeAg-negative, were on adefovir (a more toxic cousin of tenofovir) for 4-5 years with undetectable viral loads, then the med was stopped and the patients followed 5.5 years. All had a viral rebound in the first few months and 76% had biochemical relapse. These viral rebounds and increased ALT levels were transient and reversed spontaneously even in the group of 18 patients who did not resume antiviral therapy.  In fact, 15 patients who did not receive additional therapy had sustained remissions at the end of the first year, increasing to 18 after 3 years!! And by the end of follow-up, 13/18 (72%) cleared their HBsAg!!! The thought was that there was pretty consistent viral rebound early, but that the prolonged suppression of HBV (by effective treatment for 4-5 years) modulated the immunologic response so that the innate immune system was able to clear the hepatocytes that had resumed HBV replication and were able to contain the virus (similar to what happens in patients effectively treated with interferon alfa).
  • The above systematic review was a difficult one to interpret, since there was pretty great heterogeneity among the studies, including no consistency in when to consider stopping meds, definition of relapse, definition of VR, consensus on when to restart therapy, etc. But, bottom line seems to be that there is a pretty good chance of sustained viral and biochemical remissions in patients with chronic hepatitis B, even those who are HBeAg-negative, after stopping meds (though in this case, one should wait at least 2 years and probably more of having a suppressed viral load, and should anticipate a short-term flare in viral and biochemical markers), though it is important to have close follow-up for at least one year. And the newer meds (entecavir, tenofovir) seem to have a pretty consistent low level of developing resistance. So there does not seem to be much of an issue of developing resistance by stopping and restarting these meds. And, for several of my patients on meds for chronic hepatitis B beginning in their youth, the prospect of not taking meds for the rest of their lives is an appealing one. Though I would be hesitant to stop meds in a patient with pre-existing cirrhosis at this point, given the limited data and the above-noted death.

Primary Care Corner with Geoffrey Modest MD: Zika Guidelines/Updates from CDC

18 Feb, 16 | by EBM

By Dr. Geoffrey Modest

A brief update on a few developments with Zika virus:

The CDC came out with new recommendations on reducing sexual transmission of Zika (see​ ).

  • There are a few cases of very-likely sexual transmission of Zika: one mentioned in prior blog: ), and a recent one in Texas.
  • There was a report of a replication-competent Zika virus isolated from a Tahitian man at least 2 weeks and up to 10 weeks after Zika illness onset (the virus might persist in semen after it is no longer detectable in blood). He reported no sexual contacts
  • There are not a lot more data: i.e., we do not know the actual length of time that replication-competent Zika virus​ is present in semen; we do not know if men with asymptomatic disease (which seems to happen in 80% of infections) have the virus in their semen, and if so then for how long; or if the virus is of sufficient quantity to be transmissable; if condoms are in fact completely protective (not the case in all viruses, e.g. HSV); if men can develop Zika (symptomatic or asymptomatic) from infected women; how robust and longstanding is immunity after an initial infection?
  • So the recommendations regarding sexual transmission and ways to prevent it are largely guess-work, erring to being overly cautious, and are likely to be modified as our understanding increases. The current recommendations:
    • Men with pregnant partners: if the man resided in or traveled to an area with Zika, either abstain from sexual activity or consistently and correctly use condoms. This includes vaginal, oral or anal sex. Pregnant women should mention this to their obstetric providers and should consider Zika virus testing even if they are asymptomatic (see for updated guidelines).Since we do not know how long viable virus is present in semen, the CDC does not say when it is okay to resume unprotected sex.
    • ​Men with nonpregnant sex partners: if the man resided in or traveled to an area with Zika, he ​”might consider abstaining from sexual activity or using condoms consistently and correctly during sex” (again, not sure for how long). At this point testing men for the purpose of assessing risk is not recommended (we need to know a lot more about the incidence, consistency, and duration of viral shedding in semen).

Also, there are news reports of Zika transmission by blood donation, and virus detection in saliva and urine. Again, unclear if these are important means of viral spread. We need lots more information. But it is interesting that this virus has been around since first identified in 1947. This is not new (though it would be good to know for sure if the virus has mutated): why is there so little information? Because of inadequate surveillance in rural Africa? Because perhaps the virus has been around for a lot longer than that and there was a lot of immunity already there? Or it infects little kids who are then immune and not able to acquire a new infection when pregnant later? And the new outbreaks in Brazil and elsewhere reflect the rapid spread in a nonimmune community replete with lots of mosquito vectors and enough infected people coming from Africa or other more endemic areas?

A couple of other points. My guess (assuming this is the same virus as in 1947) is that Zika was prevalent then, infected kids, was not such a serious infection, and created long-term immunity. Again, this is highly speculative, but on my searching around, there were no reported cases of microcephaly in Africa (suggesting that pregnant women were not susceptible to the virus, which suggests that they were infected as kids and that they had longish term immunity). And I am concerned that there may well be nonhuman reservoirs which help the virus spread (both given the rapidity and extent of the current outbreaks, and a finding in the rain forest in Nicaragua that 40 howler monkeys were found dead with no evidence of trauma or other clear cause). The sort-of-good-news is that Zika is similar enough to other flaviviruses that it is likely that we can develop a vaccine pretty rapidly (i.e., 1.5 years vs 3-4 years).

As of 2/11/16: Western Hemisphere countries with confirmed local transmission: Chile, Brazil, Colombia, Suriname, El Salvador, Mexico, Panama, Venezuela, Honduras, French Guiana, Martinique, Puerto Rico, Bolivia, Saint Martin, Haiti, Barbados, U.S. Virgin Islands, Dominican Republic, Nicaragua, Jamaica, Costa Rica, United States

Dr. Paul Sax, a prolific ID specialist from the Brigham and Women’s Hospital in Boston, has a blog with 12 questions about Zika and his answers. The direct URL to his blog does not seem to be working, so I will take the liberty of pasting his questions/responses:

  1. I’m pregnant or know someone who’s pregnant. Can I/she travel to — [insert country close to one of the countries that has Zika transmission,but is not currently listed]?  Yes … but … with a caveat. It’s a highly dynamic situation, and just like dengue and chikungunya, Zika is likely to be reported in many of these adjacent countries soon (especially in the Caribbean). Not only that, incidence frequently rises quickly in countries after they first report the disease. So why not change those travel plans if possible?
  2. I’m pregnant or know someone who’s pregnant. Can I/she travel to Florida (or Alabama or Mississippi or Louisiana or Texas or Hawaii)?   There has been no mosquito-borne Zika transmission in the USA yet, though likely there will be sporadic cases soon. But just like dengue and chikungunya, it seems that a widespread outbreak is unlikely — we have more resources for mosquito control, and way more air conditioning.
  3. How long after returning from [insert Zika country here] can someone safely get pregnant? After all, since 80% of people who get it are asymptomatic, how does one know if Zika infection even occurred?  We don’t know the precise duration of viremia for Zika, or whether the duration of viremia correlates with symptoms. (My gut feeling is that it will, but who knows.) Estimates are that viremia clears on average in about a week. So right now it seems prudent to wait at least a couple of weeks after returning before trying to get pregnant, maybe a month to be on the safe side.
  4. A guy travelled to [insert Zika location here]. How long after travel should he wait before having sex with his pregnant partner?We don’t know how long Zika virus remains in semen after infection, nor (again) whether this duration correlates with symptomatic infection (again, my guess is that it does). Since Zika acquisition during pregnancy is what we’re trying to avoid, these guidelinesrecommend abstinence or condom use during the pregnancy, which makes sense to me. Now what about the more common scenario, partner isn’t pregnant? Next question, please.
  5. A guy travelled to [insert Zika location here]. How long after travel should he wait before having sex with his non-pregnant partner? The guidelines linked in the previous question state that these couples “might consider abstaining from sexual activity or using condoms consistently and correctly during sex,” but no duration for this “safe sex” practice is given. Note the use of the word, “might” — this is CDC parlance for, “Look, we’re not going to tell you that doing nothing is totally safe, but we don’t feel that strongly about this recommendation.” (Check out the rabies guidelines for plenty of “mights” in this mode.) After all, Zika infection is pretty mild, and there have only been 2 documented sexual transmissions. In fact, one could argue that if other forms of contraception are being used, that transmitting the infection would have a benefit — namely, immunity for a future pregnancy. For worried folks, I’ve been saying they “might” as well wait a month. For unworried folks, I’m not saying anything. Importantly, there is no evidence that prior infection with Zika will have a negative impact on future pregnancies, once the infection clears.
  6. Can’t the woman who wants to get pregnant — or even the guy with the pregnant partner — just get a Zika blood test when they return from a Zika country/region, and find out if they were infected? That would make us all less anxious.  Not yet. Zika testing is now done mostly through CDC (someone from Florida told me they had local access to testing), and there isn’t the capacity to test everyone. This is why testing is now recommended only for pregnant women who were in Zika transmission areas. Initially it was recommended only for women with symptoms; this was broadened last week to include allpregnant women, even those without symptoms. And remember, the test isn’t so great — there is extensive cross-reactivity with dengue and prior Yellow fever vaccination. So while it would be ideal to have a widely available, rapid, and accurate Zika test, our current test misses on all these marks. I suspect (hope) this will improve shortly.
  7. I read a vaccine is in the works. When will it be available?Vaccines take years to develop, and many, many millions of dollars. While some have stated that it should be technically feasible to produce a Zika vaccine, that doesn’t mean it will work in humans, or even that if one does work, that it will be marketed. So put this one on the way back burner (unless you’re a vaccine researcher).
  8. The virus was discovered decades ago. Why hasn’t the link to microcephaly been reported before?  A couple of theories, not mutually exclusive: 1) It is likely that in areas where Zika is already established, initial infections predominantly occur during the pre-childbearing years, which induces immunity. 2) The incidence of an infection is often highest after infections enter a community for the first time, as the pathogen encounters a large pool of susceptible hosts. In areas with established infection, the combination of some regional immunity and lower incidence means that fewer women acquire the infection during pregnancy — making it much harder to identify an association.
  9. I read that some countries with Zika transmission are recommending that women delay pregnancy — isn’t the virus still going to be around for years to come, maybe indefinitely? They can’t be expected to delay having babies indefinitely. This is a controversial recommendation, and indeed the WHO does not endorse it. However, it makes some sense, largely for the reasons cited in the previous question — the delay could allow immunity-inducing infection to occur in some non-pregnant women of childbearing age. Even if this doesn’t happen, the incidence of infection should be sharply lower once a substantial fraction of the population has been infected.
  10. How do we know that Zika even causes microcephaly? I’m a skeptic.It’s true that we don’t know definitively that Zika causes microcephaly. And it’s highly likely that reporting bias has to at least some degree increased the number of cases, especially in Brazil. But the number of cases reported in Zika-transmission countries is many fold higher than usual, beyond what public health officials would consider solely the result of reporting bias — read this excellent piece in the New York Times, which conveys vividly what was happening as the epidemic accelerated. Lending further support to the connection, researchers have isolated the virus from babies with microcephalyand there are now reports that French Polynesia may well have had an increase in CNS abnormalities in babies around the time that their Zika outbreak occurred in 2014. Finally, one needs to consider the source of the travel advice — our CDC is very cautious about issuing such travel warnings (substantial geopolitical and economic consequences), and would not make this recommendation unless the evidence were very strong.
  11. How about Zika and the Guillain-Barré syndrome syndrome?Though there have been reports of Guillain-Barré syndrome after Zika virus infection, whether Zika causes this neurologic syndrome is not conclusively established — more research is needed here, though again the anecdotal data are suggestive. There are, of course, other infections linked to Guillain-Barré, most notably campylobacter, so the association is plausible.
  12. I hear the virus can be transmitted not just by Aedes aegypti, but also the much more widespread Aedes albopictus. Isn’t it just a matter of time before this virus is charging through the United States like it is through Central and South America?  With the important upfront caveat that prognostications on disease spread are notoriously iffy, experts in vector-borne illnesses do not think that this scenario is likely — related to the lower “efficiency” of viral transmission from Aedes albopictus,and the experiences to date with dengue and chikungunya. But sure, there will always be worst-case scenarios — and noisy champions of these views who get lots of attention

Primary Care Corner with Geoffrey Modest MD: FDA Response to Prescription Opioid Abuse

17 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The FDA published a “proactive response to prescription opioid abuse” in New Engl J Med (see$db.getCUSTOMERID()&jspc=$db.getSPECIALTY(). This article reflects the direction they plan to follow:


  • In the course of one year, 100 million people in the US suffer from pain; 9-12 million have chronic or persistent pain. All should benefit from pain relief
  • But, there are increasing issues of addiction, diversion, and death (19,000 overdose deaths in 2014)
  • Around 300 million opioid prescription are now written annually in the US


  • They asked the National Academy of Medicine (NAM, used to be the Institute of Medicine) to help develop a regulatory framework for opioid review, approval, and monitoring, one which balances the individual’s need for pain control with the broader public health/societal issues (this process will take a pretty long time)
  • The FDA’s Science Board will meet in March to discuss the role of meds in pain management, development of alternative pain meds, and post-marketing surveillance (as a means to address the more immediate concerns)
  • Special focus will be on extended-release or long-acting opioids, including extensive post-marketing research (11 mandated studies) around safety concerns. Also manufacturers of these long-acting preparations will be subject to a Risk Evaluation and Mitigation Strategy (REMS) requiring them to fund voluntary CME courses around these products. The FDA will also require mandatory provider education
  • Support the development of abuse-deterrent formulations of opioids, as well as countermeasures (e.g. naloxone, intranasal or via auto-injector) and ways to improve their access
  • Prioritize the development of non-opioid alternatives for pain relief
  • For children, focus on making sure that evidence-based medicine is used to identify appropriate indications and dosing, with a focus on safe and effective opioid prescribing, and reduce use for inappropriate indications. The Pediatric Advisory Committee will address specifics
  • They acknowledge the elephant in the room: “the field of chronic pain treatment is strikingly deficient in …scientific evidence … to assess the risk and benefits of intended use of medical products”, and that a key lesson learned by the FDA is the need for continued research. The risks are clear, and there are reasonable data on the benefits of non-opioids. But not a lot of data on the long-term benefit of opioids themselves

For older blogs on chronic pain management and opiates, see This includes a rather striking blog on the use of appropriate provider-prescribed opiates in kids (e.g., post-surgery) and their subsequent opioid misuse (these were kids who had a low pretest probability of doing so).

The blog/critique of the CDC recommendations of Dec 2015 (which are being reviewed because of lots of negative public feedback — see: . Though I should add that the FDA noted in the current article that they are “supporting the CDC’s Guidelines for Prescribing Opioids for Chronic Pain”).

Primary Care Corner with Geoffrey Modest MD: Rivaroxaban, Is It Really Better Than Warfarin for Non-valvular Atrial Fib?

16 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The BMJ spotlight team (actually Deborah Cohen, associate editor) just released another investigation into poorly-regulated drug-company-supported studies which have led to large changes in clinical practice and large profits for drug companies (see BMJ 2016;352:i575). This one is a challenge to the ROCKET-AF study (see N Engl J Med 2011;365:883-91), which was the single study leading to FDA approval for rivaroxaban, a​ direct thrombin inhibitor, by showing that although it was as good as warfarin in patients with non-valvular atrial fibrillation in preventing strokes, there were fewer episodes of intracranial and fatal bleeds. Of note, rivaroxaban is now the world’s best-selling new anticoagulant. However, it turns out that the ROCKET-AF study relied on defective point-of-care INR machines which gave falsely low INR levels, thereby leading the researchers to increase the warfarin dosing and perhaps predisposing patients to more bleeding.


  • BMJ found that the INR devices used had been recalled in December 2014 because the FDA issued their highest level recall notice finding that these devices could give “clinically significantly lower” INR values. The device manufacturer Alere had received 18,924 reports of malfunction and 14 serious injuries, dating back to 2002 (prior to the ROCKET-AF trial starting)
  • September 2015: BMJ asked ROCKET investigators about the device recall. No direct response, just one from the drug company that they were unaware of the recall.
  • The European Medicines Agency (EMA, the European equivalent of the FDA) in April 2015 did not know these devices were used in the ROCKET-AF study, and called for an independent investigation into direct oral anticoagulants. The company claimed that the results of ROCKET-AF were still valid after conducting some sensitivity analyses. No independent investigation has happened to date.
  • But, as per Harlan Krumholz, a cardiologist at Yale, “the study should be considered of uncertain validity until a more thorough review can be  done”, and to have “an investigation by an independent group of experts to quickly determine if there are grounds for retraction [of the study]”.
  • In looking back at the original FDA approval for rivaroxaban, 2 primary reviewers had expressed concern about the warfarin control and recommended that the drug not be approved, stating “ROCKET provides inadequate information to assess the relative safety and efficacy of [rivaroxaban] in patients whose warfarin administration can be well-controlled”
  • BMJ asked the ROCKET researchers if those patients who had major bleeds had had laboratory INRs checked. None responded.
  • It turns out that at the 12-week and 24-week time-periods, there were simultaneous measurements of INR by device and a central lab, though this data has not been released.
  • There was a rebuttal by the investigators to the above BMJ charges (see DOI: 10.1056/NEJMc1515842). The investigators did post-hoc analyses using the FDA recall criteria [medical conditions that the FDA thought might lower the INR value of the device: anemia with hematocrit >30%, and conditions which raised fibrinogen levels (acute inflammation, chronic inflammatory conditions, severe infection, cancer or end-stage renal disease]. Results of the post-hoc analysis were mixed:
    • ​In those without recall conditions: no significant difference in strokes with rivaroxaban vs warfarin; more intracranial hemorrhages, fatal or critical organ bleeding with warfarin; more GI bleeding overall with rivaroxaban
    • In those with recall conditions (and presumably on unnecessarily higher doses of warfarin): decreased stroke in those on rivaroxaban but only in the per-protocol patients; no difference in intracranial hemorrhages, fatal/critical organ bleeding; more GI bleeding with rivaroxaban.

So, these articles bring up several issues:

  • It is a little unsettling to me that rivaroxaban was approved based on only one drug company-sponsored study
  • I’m not sure what to make of the post-hoc analysis by the investigators. Surprisingly, they seem to show fewer adverse events in those without the FDA-designated recall conditions, though interestingly in those patients with those conditions, rivaroxaban​seemed a bit worse on clinical bleeding. But are those recall conditions complete? Many older studies, for example, found a relationship between smoking and high fibrinogen levels (to the point that many posited that the main mechanism of smoking causing heart disease was mediated by fibrinogen, and that stopping smoking quickly reversed much of the increased CAD risk because smoking’s effect on fibrinogen levels reversed so quickly). Smoking was not on the recall list. Are there other unknown conditions which lead to aberrancies in the device INRs?Or are there other unknown biases which can happen in a post-hoc analysis? It would be interesting to know the relationship between the laboratory INR measurements at the 12 and 24-week times and the results of the point-of-care devices. And what the correlation was on an individual basis between these discrepancies and the positive and negative clinical outcomes. And, I would strongly support an independent review.
  • A prior BMJ issue and several other studies have suggested that dabigatran also may have many more adverse events than reported and that there were drug company shenanigans; in particular the drug company covered up evidence suggesting that there needed to be blood monitoring, despite the main selling point for the drug being that no drug monitoring was necessary, as opposed to warfarin and the need to follow INRs, (see As a result of the BMJ and other articles about dabigratan, at the end of 2015 both the EMA and FDA held meetings to see if there was a need to monitor blood levels of direct anticoagulants and adjust the dose as necessary to maximize benefits/minimize harms.
  • This raises the issue that the FDA historically has been less aggressive in regulating devices than meds. Typically, once one device is accepted, there is much less overview on similar products (new devices just need to be “substantially equivalent” or similar to ones already on the market). And, the issue of rivaroxaban highlights that approval of meds may well require studies using not-so-well-regulated devices which could potentially dramatically affect the results. And, this is compounded by the selection bias favoring the drugs: positive studies of drugs are published at a much higher rate than negative studies. And once a drug company has a positive study (as with ROCKET-AF), there is little incentive to do further confirmatory studies after a drug is approved.
  • So, yet again, I am very hesitant to prescribe these newer meds, given huge conflicts-of-interest, the large numbers of cases of drug companies hiding results they do not like, the decreasing authority and efficacy of the FDA in monitoring new drugs (e.g., see ), and the increasing reliance on post-marketing surveillance, which seems to happen only pretty rarely (e.g., see ). I continue to use warfarin as my preferred anticoagulant, and I use the close monitoring of INRs (which in rock stable patients, can actually be done on an every 2-3 month basis) as a means to check-in with these patients, who are typically medically-complex anyway.

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