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Primary Care Corner with Geoffrey Modest MD: ?Add PPI to aspirin in elderly

20 Jun, 17 | by gmodest

by Dr Geoffrey Modest

A prospective population-based cohort study of patients with vascular disease and on antiplatelet therapy (mainly low-dose aspirin) found a dramatic increase in the risk of bleeds in those over 75 years old, raising the question of whether we should be using proton-pump inhibitor (PPI) prophylaxis (see



— 3166 patients with vascular disease (defined as a 1st TIA, ischemic stroke, or MI and placed on antiplatelet therapy) in the Oxford Vascular Study from 2002 to 2012 were followed until 2013. 50% of the cohort were greater than 75 years old

— for the subgroup of patients < 75 years old:

— mean age 61, 65% male, 32% ischemic stroke/30% TIA/21% NSTEMI/17% STEMI, 97% on aspirin/3% nonaspirin antiplatelet therapy

— for those > 75 years old:

— mean age 83, 43% male, 42% ischemic stroke/27% TIA/23% NSTEMI/8% STEMI, 95% on aspirin/5% nonaspirin antiplatelet therapy

— the predominant aspirin formulation was 75 mg enteric-coated aspirin



— there were 405 1st bleeding events (187 major bleeds) during 13,509 patient years of follow-up in the cohort, at an average annual risk of 3.36%:

— 218 gastrointestinal

— 45 intracranial

— 142 other

— risk of non-major bleeding was unrelated to age, but major bleeding increased steeply with age, particularly in those > 75 years old, with no increase with age in patients < 70

— for those >75 yo vs <75 yo:

— major bleeding overall, HR 3.10 (2.27-4.24), p<0.0001 [ie, more than 3-fold the risk]

— fatal bleeds, HR 5.53 (2.65-11.54), p<0.0001

— major upper GI bleeds, HR 4.13 (2.60-6.57), p<0.0001; and fatal GI bleeds, HR 10.26 (4.37-24.13), p<0.0001.

— The annual risk of major bleeds increased steeply after age 70, reaching 4.1% at age 85 or older, with a similar pattern for both life-threatening and fatal bleeds. Those > 75 yo had more severe bleeds in those younger, p<0.0001. The outcome for nonfatal bleeds was also worse in the older group.

— Also, the proportion of those who survived extracranial bleeds which resulted in new or a sustained increase in disability increased with age, OR 12.8 (4.5-36.6), p<0.0001, comparing those > 75 vs <75 yo, especially in those with upper GI bleeds

— this analysis was similar if those on dual antiplatelet treatment (e.g. aspirin plus clopidogrel) were excluded

— the association of major bleeding with age were independent of sex, history of vascular disease, vascular risk factors, and history of peptic ulcer disease

— the absolute risks of major bleeding vs ischemic events increased with age. In the younger cohort this ratio was similar to those in prior aspirin trials. But the ratio increased from 0.19 in those younger than 75, to 0.32 in those 75 to 84, to 0.46 in those older than 85 [ie, the risk of major bleeds estimated to be attributable to antiplatelet treatment was approaching that of prevented ischemic events].

— The estimated number needed to treat (NNT) with routine PPIs to prevent one disabling or fatal upper GI bleed over 5 years would be 338 for individuals < 65 years old, but only 25 for individuals > 85 years old. The NNT to prevent one major upper GI bleed at 5 years was 80 for patients younger than 65, 75 for patients 65-74, 23 for patients 75-84 and 21 for patients greater than 85.



— given the high prevalence of vascular disease in people over 75, 40-66% of individuals in the US and Europe take aspirin or other antiplatelet drug for secondary prevention of vascular disease (and this does not include primary prevention use of aspirin!!!!). Guidelines in general do not recommend taking PPIs regularly, though a meta-analysis of randomized PPI trials vs placebo in patients on antiplatelet drugs, mostly aspirin, found a 74% reduction in upper GI bleeding (this was the number they used in estimating the preventive efficacy of PPIs above).

— The general basis for recommendations for use of antiplatelet agents is largely based on trials done in people < 75 years old (the mean age was 63, and most were < 75 yo).

— As a perspective in this study, PPIs would presumably only prevent upper GI  bleeds, though 60% of all bleeds and 48% of major bleeds in the above study were non-upper GI bleeds

— assumptions in the above study, as noted by the authors, are that the efficacy of PPIs would be similar for the prevention of any bleed vs major bleed, similar at different ages, and remain consistent over time.

— I am very concerned about the role of H Pylori infections in predisposing patients to upper GI bleeds when they are on NSAIDs.  An article in 1997 changed my practice to test and treat people prior to starting regular NSAID therapy (see Chan FKL Lancet 1997; 350: 975, which found that patients about to begin longterm NSAID therapy, had endoscopy, and those found to have asymptomatic H Pylori infection were then were randomized to either naproxen 750mg/d vs triple H Pylori therapy and then naproxen 750 mg/d, finding that on repeat endosopy 8 weeks later, 26% had ulcers in the naproxen only group whereas 3% had them after successful H Pylori treatment). Subsequently the 2008 Expert Consensus document by the Am Heart Assn and Am College of Gastroenterology recommended: “Testing for and eradicating H. pylori in patients with a history of ulcer disease is recommended before starting chronic antiplatelet therapy.”  (see JACC 2008; 52: 1502). And another more recent article finding that those on low-dose aspirin who had H Pylori infection which had  been eradicated had recurrent GI bleeds at the level of  average-risk patients (see Chan FKL. GASTROENTEROLOGY 2013;144:528–535​)


So, as per many prior blogs, I am concerned with long-term, wide-scale use of PPIs, in terms of significant adverse effects, as well as their profound effects on the microbiome. Given the rather compelling data from this study, it would be really great to have a randomized controlled trial in patients for both primary and secondary atherosclerotic disease prevention with aspirin, comparing PPI vs H2 blocker (fewer adverse longterm effects than PPIs) vs placebo, looking at both major GI bleeds as well as comparing them to the incidence of thromboembolic events. And, as per above comment, it would be great to either exclude those who were H Pylori positive, or treat them prior to aspirin therapy. My own practice in general, as mentioned in prior blogs, is to test and treat H Pylori infections, given their profound frequency in my patient population and the association with stomach cancer (I have had several older patients die from stomach cancer, which might have been prevented if H Pylori were diagnosed and treated earlier: eg see here ). Besides, it is always a tad unnerving when we have to prescribe a medication (which is not entirely benign) to counteract the effects of another medication.​ But, based on the study, it does seem reasonable to consider a PPI in those greater than 75 years old and on aspirin therapy.

Primary Care Corner by Geoffrey Modest MD: Risks and benefits of longterm PPIs

26 Apr, 17 | by gmodest

​by Dr Geoffrey Modest

The American Gastroenterological Association (AGA) just published a clinical practice update on the risks and benefits of long-term use of proton pump inhibitors (see  ).



RISKS: (these are the authors’ assessment of the quality of the evidence and the effect sizes)

kidney disease: 2 retrospective observational studies found a modest effect size (10-20%) of CKD in those on PPIs, with very low quality of evidence. Mechanism, unclear: ? if those on PPIs had more comorbidities which predispose them to kidney disease?

dementia: retrospective observational studies finding a modest effect size (4-80%), with very low quality of evidence. Presumed mechanism: microglial cells use certain ATPases to degrade beta-amyloid, and PPIs may block these ATPases (which does increase beta-amyloid in mice)

bone fracture: many observational studies, data inconsistent, modest effect size (39% to 4-fold increase), with low to very low quality of evidence. Presumed mechanism: hypochlorhydria-related malabsorption of calcium or vitamin B12, gastrin-induced parathyroid hyperplasia, and/or osteoclast vacuolar proton pump inhibition.

myocardial infarction: though a very small effect was found in an observational study, none found in RCTs. Presumed mechanism: omeprazole decreasing clopidogrel levels and its anti-platelet effect, but a randomized controlled trial comparing those on clopidogrel versus those on clopidogrel plus omeprazole had no difference in cardiovascular event rates.

small intestinal bacterial overgrowth: small studies have found that PPIs lead to bacterial overgrowth in the duodenum/small intestine, only some of which were symptomatic, modest effect size (2-fold to 8-fold increase), low quality of evidence. Presumed mechanism is loss of the bactericidal effects of gastric acid by taking PPIs

non-typhoidal salmonella and Campylobacter infections: increase found in 1 study, not confirmed. modest effect size (2-fold to 6-fold increase). Presumed mechanism: achlorhydria (and studies show that those with pernicious anemia or gastric surgery-induced achlorhydria do seem to have increases in these infections)

spontaneous bacterial peritonitis: observational studies suggest a 2-fold increased risk of SBP (50% to 3-fold increase), very low quality of evidence. Proposed mechanism: achlorhydria leading to gut bacteria changes, leading to changes in intestinal permeability and translocation of bacteria across the intestinal wall

C. diff infections: observational studies suggest 50% increased risk of C diff infection; and changes in bacterial taxa associated with C diff were increased in healthy volunteers after 4-8 weeks of high-dose PPIs. (the risk still pales compared to the rate of C diff with antibiotics). Risk may be higher in children, modest effect size (no increase to 3-fold increase), quality of evidence: low. Proposed mechanism: downstream effects of PPIs on colonic microbiota (see comment below)

pneumonia: seems to be more frequent soon after starting PPIs than after longer-term treatment.   Raises question of perhaps the PPIs were erroneously started for early misdiagnosed pneumonia. pneumonia is not a consistent finding in other studies, modest effect size (though no association in RCTs), very low quality of evidence. Proposed mechanism: upstream effects of PPIs on oropharyngeal microbiome

micronutrient deficiencies (overall 60-70% increase), low or very low quality of evidence:

–Calcium: may be decreased absorption, but not of water-soluble calcium salts or calcium from milk or cheese.

–Iron:  inconsistent data. No association in some Zollinger-Ellison patients on 6 years of PPIs, some association in other studies

–Magnesium: rare cases of profound hypomagnesemia. Observational data on modest positive association

–vitamin B12: most studies finding around 2.4-fold increased risk.

gastrointestinal malignancies: data also mixed. Suggestive data of increased risk in those with untreated H pylori infections, and concern about the profound hypergastrinemia (which has trophic effects on colonic epithelial cells in mice and on human colorectal cancers in vitro),  but population-based retrospective studies have failed to confirm a relationship. (No association in RCTs), modest effect size, very low quality of evidence.



In terms of benefits of PPIs, there are basically moderate to high quality studies supporting their use in:

— GERD with esophagitis or structure (though may not be necessary with non-severe esophagitis, and no long-term data)

— GERD without esophagitis or stricture (though may not be necessary with relatively mild symptoms, and no long-term data)

— Barrett’s esophagus with GERD (no long-term data)

— NSAID bleeding prophylaxis (no long-term data)

— Barrett’s esophagus without GERD (this has low quality of evidence from observational studies only: no RCT, mostly mechanistic thinking that chronic inflammation may lead to esophageal adenocarcinoma and some observational data. But I would also be concerned that these data are based an unusual subset of patients who are asymptomatic yet have had endoscopy that documents Barrett’s, and even observational studies are therefore a tad suspect).



–It is not surprising that the quality of these studies on benefit is higher than the above studies of adverse effects, since these were designed explicitly as intervention trials to look for benefit, probably all supported by drug companies, and controlling for co-morbidities, etc.

–I am also a little concerned that the AGA may be biased towards PPIs, perhaps because gastroenterologists tend to see patients with more severe conditions requiring PPIs, or perhaps financial conflicts-of-interest (as with all specialty societies, since the top academic specialists who often write the guidelines tend to be involved in drug-company-sponsored research).  My real concern with PPIs is that many many outpatients are put on PPIs for marginal reasons, and that very few patients are stepped-down to less aggressive therapy. As mentioned in prior blogs, given the limitations of time a primary care clinician has with patients, when their stomach problem is better with PPIs, it is time to deal with the myriad of other problems, keeping up with standard health maintenance issues, etc etc. The issue of the above potential complications of PPIs are very probably less important clinically than the need for PPIs for those with very clear indications (though I am a bit concerned that these studies are all short-term and it is a bit tenuous to extrapolate to long-term harms). But, the preponderance of studies finding some association of potentially serious adverse effects from PPIs, whether the studies are great or not, reinforces the imperative to avoid using PPIs unless clearly indicated, and, when appropriate, to step-down therapy as soon as possible. My experience is that patients who have endoscopy for dyspepsia are essentially invariably put on PPIs by the gastroenterologists independent of endoscopic findings. And, I have had pretty good success in getting some patients off of them, sometimes just onto prn calcium tablets or H2 blockers. But this may be a time-consuming issue to deal with. And I certainly have many patients for whom either I do not have the time to pursue or who are resistant to stepping down on therapy.

–To me, there is also the perhaps significant general omission in the above article of the effects of PPIs on the microbiome (see here). My guess is that these effects do not necessarily translate clinically into disease, which is not so surprising given the complexity of this process, the multiple variables involved, and the length of time necessary to develop detectable disease (and the studies are too short). But, PPIs are associated with changes in the colonic microbiome to a less healthy one: with significant increases in Enterococcus, Streptococcus, Staphylococcus, and potentially pathogenic E coli species, as well as oral bacteria of the genus Rothia. And decreased Clostridiales.  These changes have been thought to lead to the association with C diff infections, but perhaps with other even unsuspected long-term harms. Though not mentioned specifically in the above article, these microbiome changes do add further credence to the imperative (I think) to minimize PPI usage.

So, my bottom line: PPIs are way overused for marginal indications (it is easy to jump to PPIs for dyspepsia, since they work so well…), but we should really discourage the use of PPIs unless they meet a clear criterion as above, or try to use the step-up approach: start with calcium or H2 blockers, then increase to PPIs when needed, and still try to step-down later; and try to get patients off of PPIs when they have been on them for awhile, unless there is a clear indication to continue.  Though a complicating factor here is that they are available OTC….

for another recent blog on PPI risks and benefits and some additional concerns, see here.


Primary Care with Geoffrey Modest MD: Lessons I’ve Learned From Looking at the Medical Literature

21 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There have been several concerning issues and lessons that I have learned in the process of doing these blogs over the past several years (I am sending out this email/blog as a follow-up to some of the methodological issues and perhaps incorrect assumptions inherent in many clinical studies and their application to actual patients, as noted in the recent blog on placebos. See

  • Meta-analyses:
    • There is huge variability in the actual utility of meta-analyses in making clinical decisions. these analyses are mathematical concoctions which try to combine different studies with usually very different people (different inclusion/exclusion criteria, people with different levels/types of comorbidites, different ages, different ethnicities, often different doses of the med being assessed, even somewhat different outcomes measured). And the meta-analyses themselves have different inclusion criteria (minimum number of people in a study that they include, the authors’ assessment of the quality of the study). And they use different statistical analyses (e.g. some do propensity score matching as a means to control mathematically for different patient baseline characteristics; or they may use different basic statistical analyses). Also, in some cases the meta-analysis is overwhelmed by a single very large study (i.e., a meta-analysis with 10 studies, but the one with many more patients will give much more statistical weight to that one study, even if the smaller studies were actually methodologically better). As a result I have seen almost simultaneous meta-analyses on the same subject in different journals coming to different conclusions.
    • There was a really good article looking at the pyramid of the value of different types of clinical evidence (see , or Evid Based Med2016;21:125-127 doi:10.1136/ebmed-2016-110401 ) which, unlike other “evidence pyramids” in the literature over the past 20 years, dismissed meta-analyses/systematic reviews, and highlighted, for example, that study design itself (i.e. an RCT) does not necessarily mean that it is a “better” study and should be the one influencing clinical practice just because of its design, over a good cohort study (they demonstrate this by their schematic pyramid of evidence-based medicine having wavy lines separating the types of studies, instead of straight-line clear-cut separations of the value of studies by their design. and they do not include meta-analyses/systematic reviews in the pyramid). To me, RCTs are clearly limited by their exclusion and inclusion criteria, and suffer from reductionism (see prior blogs, but basically reducing “n” patients into some mathematical average of, e.g., a 53 year-old patient, 35% female, 78% white, 37% diabetic, with no renal failure and 56% on aspirin……”), and trying to apply the results to a totally different individual patient you are treating with different ethnicity, comorbidities, meds, etc.
  • Guidelines (also not included in the pyramid of the value of evidence-based medicine, above):
    • There has been an unfortunate evolution of clinical guidelines, with a few dramatic shifts over the decades:
      • The older guidelines were written by the NIH or similar governmental organization, with an emphasis on bringing in different experts both within the field and, at least to my experience, some outside of the field (e.g. clinical people), and providing a more consistent, less biased, and independent validation mechanism for the recommendations
      • Perhaps related to ideological or financial imperatives, newer guidelines are more often being channeled back from the governmental agencies to professional societies, creating a few problems:
        • Guidelines may not reach the same conclusions: e.g. the early versions of the Am Diabetic and Am Heart Assn guidelines on blood pressure goal. Then, what is a clinician to do??
        • The professional societies’ guideline-writing groups often do not include practicing clinicians (at least from what I’ve seen), but mostly the higher-ups (i.e., mostly researchers) in the professional societies. There is often a significant financial conflict-of-interest with many guideline-committee members, though this is being watched and reported more now than before, more with some professional societies than others. But, beyond those direct financial/other interests of some of the specialty society leaders, I would guess that it is not easy/comfortable for others within the societies to be critical of them (they are the “leaders”, with disproportionate influence within the writing committee and within the specialty society)
        • And there are a huge profusion of guidelines, from all of these societies, to the point that it is pretty impossible to keep up with them
        • However, I think the real reason that guidelines are not considered part of the “evidence pyramid” noted above is that there is no external validation metric used for these guidelines: there are a group of specialists sitting around a table and making recommendations about how we should treat patients, and with an inherent conflict-of-interest above and beyond those of specific leaders promoting a technique or drug which they may personally benefit from. Is it surprising that the American Urological Association has historically been much more aggressive in pushing for PSA screening? Or the American Cancer Society historically pushing for more cancer screening? Or the American College of Radiology promoting more mammograms?
        • So, the best model to me is reverting to the way guidelines used to be created, as currently done in other countries having a single uniform approach to guidelines (e.g. the NICE guidelines in the UK are pretty exemplary to me: very thoroughly researched, with, I think, pretty unbiased and thoughtful recommendations), using the best external validation metric to promote the best, least-biased recommendations based on known data and relatively unbiased expert opinion and informed by practicing clinicians. probably the best we have now in the US is USPSTF, though they also have an important-to-know filter of usually needing strong support from RCTs to really endorse an approach (e.g., see which does not recommend lipid screening in adolescents, despite what I think is pretty compelling though circumstantial evidence, basically because there are no good 30-40 year studies following 12 year-olds, randomized to diet/exercise/perhaps meds at some point, and looking at clinical outcomes).
  • Using on-line sources for quick guidance (e.g. Up-To-Date, etc.)
    • These are also not on the “evidence pyramid”, for reasons similar to the guidelines issue: the entries are the non-validated opinions of a few individuals about how to evaluate, diagnose and treat patients. There are no upfront disclosures of commercial interest (if you click on an author’s name, then on disclosures in Up-To-Date, you can get the info, but it is a few clicks away, and, I would guess that a busy clinician looking for a quick answer probably does not do this a lot. And then the information is that the author gets money from perhaps a specific drug company. And, I would also guess, most of us primary care clinicians have no idea which meds that drug company makes and therefore which suggested med in the Up-To-Date review might be promoted more…).
    • That being said, I do not know a clinician (including myself) who does not use one or more of these sources pretty often, to get quick guidance about what to do with the patient in front of them….  it is so easy, typically has a review of the relevant studies, and gives very clear guidance. The only issue is bias and reliability…..
  • Misquoting references
    • As mentioned in a few blogs, sometimes the articles misquote references, claiming incorrectly that a previous study came to a certain conclusion. So, it is useful to check the original article when an article makes a statement about another article that seems out-of-line. This is a lot of extra work, though way easier than it used to be (often you can click on a hyperlink of the reference, or do a quick online search. Easier than going to the library…)
    • Even more commonly (still not very common), articles sometime make reference to a citation which is incorrectly cited (i.e., you look at the article cited and it has nothing to do with the author’s point??An error by the author/journal editor in making sure that the citation matches??)
  • Supplemental materials
    • Oftentimes, some of the most important material is relegated to the supplemental material (including important subgroup analyses, methodologic issues, data backing up some of the article’s conclusions, conflicts-of-interest, etc.) which really give lots of insight into the real value of an intervention. These are only accessible online (an issue if you do not subscribe to that journal) and are, I think, a significant impediment for many clinicians to access. In cases where I cannot get a specific article and have emailed the author for a copy, I only get the PDF, and unless I want to pay $30-50 to get the article through the journal (which I am not), I cannot see the supplementary materials.
  • Using not-so-relevant clinical endpoints
    • There has been a trend to using composite endpoints (perhaps to make the likelihood of an intervention’s benefit higher and more likely to be statistically significant) which just don’t make sense, such as combining a really important outcome with much less important ones. For example, a recent blog looked at CPAP for OSA (see ), assessing CPAP utility for the composite endpoint of hard cardiovascular events plus the development of hypertension. If there were benefit for significant hard cardiovascular events, I would be quite inclined to suggest CPAP for my patients. But if CPAP only decreased hypertension a little (but statistically significant), I would treat that by reinforcing lifestyle changes, or using a med if needed, and would not prescribe CPAP. Or, another example: the ADVANCE study, which looked at tight blood sugar control on the effects on hard CVD outcomes plus diabetic nephropathy. This seems pretty silly. We know from many studies that tight control helps prevent diabetic nephropathy. The more important clinical issue is cardiovascular benefit or harm. And adding a known quantity of decreasing nephropathy into the “composite” endpoint just dilutes/distorts the results. This study really highlights the general issue of lumping together non-equivalent outcomes (it is hard to argue that developing early nephropathy is somehow equivalent to, and should be numerically added to, CV deaths or nonfatal strokes; or in many other studies, lumping together all-cause mortality with need for an additional clinical procedure). I raise these issues as examples, but this is really a very common finding. And this approach of combining endpoints may be worse now, since a large percent of the studies done are designed by drug companies, etc., which have a vested interest in the most positive outcome. And sometimes one cannot disaggregate the individual outcomes without access to the supplementary material….
    • As I have railed about in many blogs, I am really concerned that the FDA accepts surrogate endpoints for some clinical diseases. The most evident one is using A1C as the end-all for new diabetes meds. Personally, I don’t really care so much about the A1c, just what really happens to patients. Many of the new drugs approved do decrease the A1c (though only a little, in most cases), yet have significant and serious adverse reactions (see many blogs in ) which undercut their utility significantly (e.g., as cited in many prior blogs: rosiglitazone does well in lowering A1C, just unfortunately increases cardiac events…)

So, I am writing this blog mostly because I have been doing these blogs for several years now, have been reading lots of articles, have the (perhaps) benefit of seeing the evolution over decades of clinical research and the medical-political-social-economic structure of both the research being done and how it is reported, and am pretty frequently struck by some of the not-often-acknowledged gaps and concerns of that literature and its effect on clinical practice. I would recommend reading the “evidence pyramid” article in the BMJ Evidence-Based Medicine journal referenced above, since it does comment a bit on some of these (and did stimulate me to write this). But, of course, I should also comment that all of the above are my observations (i.e., not validated by an independent group), but at least I have no (i.e., zero) conflicts of interest, other than the bias to a real skepticism in reading articles and guidelines, or of being an early adopter of new meds/procedures…..

Primary Care Corner with Geoffrey Modest MD: Generic Drug Price Variation for Heart Failure Drugs

18 Nov, 16 | by EBM

By Dr. Geoffrey Modest

Most of us, I believe, usually prescribe generic medications to patients, especially for patients who have limited or no insurance and have large out-of-pocket medication costs. A recent study looked at the variability of 3 generic drugs used for heart failure finding dramatic differences within similar geographical areas (see doi:10.1001/jamainternmed.2016.6955).


  • Data reflect 153 chain and 22 independent pharmacies in a 2-state region (Missouri and Illinois), across 55 zipcodes
  • They compared the cost for uninsured patients of low and high dose digoxin (0.125 and 0.25 mg/d), lisinopril (10 and 40 mg/d), and carvedilol (6.25 and 25 mg bid) for 30– and 90–day supplies.
  • They also correlated the costs with the annual income by zipcode


  • Median annual income within pharmacy zipcodes was $53,122, with a range of $10,491 – $112,017
  • The number of manufacturers was about 8 for each drug
  • Only one chain had consistent pricing across its stores
  • For a 90-day supply of the highest dose of the meds:
    • Digoxin 0.25mg varied from $10 to $910.99, with median $114.99
    • Lisinopril 40mg varied from $6.75 to $223.95, with median $34.25
    • Carvedilol 25mg varied from $6 to $208.44, with median $41.23
    • And, for all 3, $30 to $1,144.98, with median $180.46
  • Only 1.7% of pharmacies charged less than $25 for 30-day supply and 5.3% less than $100 for 90-day supply.
  • Overall, they found:
    • Pharmacy type (chain vs. independent) was not significantly associated with pricing
    • Pharmacy pricing did not vary by median annual income of the area, whether median income was $85,883, $59,347 or $31,032
    • Pricing did not vary significantly by state, or clustering by zipcode (review of their figure showed very close proximity of pharmacies with very high and very low price drugs)


  • So, pretty shocking differences in generic drug pricing, independent of the income of the neighborhood, the type of pharmacy, or drug dose/duration of therapy.
  • And, it is clear from several studies that the cost of medications does correlate with medication adherence.
  • We do seem to have a counterintuitive (and counterproductive) system in the US: patients without insurance, often those with the least income, have to pay much more for medications than insurance companies negotiate (ie, the above prices are likely much higher than an insurer would pay, even with the patient co-pay added).
  • This study only looked at 3 drugs, and though more data is needed on other meds, my own experience is that there is large variability in pricing for other drugs as well

So, bottom line: I think the study reinforces that patients without insurance really should call around to different pharmacies to check pricing. Patient should understand that there are potentially huge variations in drug costs from one pharmacy to another, even in the same neighborhood. And we really should move to a more transparent and consistent system of drug pricing in this country.

Primary Care Corner with Geoffrey Modest MD: Cardiac Drug Interactions with Statins

16 Nov, 16 | by EBM

By Dr. Geoffrey Modest

The American Heart Association just published their recommendations for managing drug-drug interactions between statins and other drugs used for cardiovascular disease (see DOI: 10.1161/CIR.0000000000000456 ). I bring this up because statins are such an important drug that we use all the time, drug-drug interactions overall are common (leading to about 3% of hospital admissions, and the result of many annoying flags in electronic medical records) and because this review goes into detail on the mechanisms of these interactions (whether through the cytochrome P-450, CYP450, system of oxidative enzymes, or those interactions involving permeability glycoprotein P-gp, a superfamily of membrane-associated ATP-binding cassette-transporters, also called multidrug resistance-1; this article gives a good review of these systems, the latter of which was pretty much unknown to me prior to seeing this article….), and the article comments on the likely clinical importance of these interactions. Of note, I did not include recommendations for fluvastatin or pitavastatin, since these seem to be used rarely. Here is a brief review of the important/relatively common drugs used in primary care:

  • Amlodipine: minor interaction with lovastatin and simvastatin (for the latter, 1.8-fold increase in simvastatin level, with recommendation to limit simvastatin dose to 20mg)
  • Colchicine: variable interaction with all of the statins, though combination “may be considered”. Monitor muscle toxicity closely. Of note, colchicine itself can cause myopathy, so can be hard to differentiate from statin-induced. Colchicine does not seem to impair CYP450 system though does seem to compete for P-gp-mediated efflux. Not much clinical data on the interaction with statins, but likely that best tolerated (based on the effect on P-gp) would be rosuvastatin, lovastatin, or pravastatin. And probably best to use lower doses of colchicine: 0.6-1.2 mg loading dose and 0.3-0.6 mg/d maintenance
  • Digoxin: not dependant on the CYP450 system. atorvastatin increases digoxin level 1.2-fold. Combo is reasonable with any statin without dose adjustment. But best to monitor digoxin levels in those on atorvastatin, esp if on higher doses.
  • Diltiazem: minor interaction with atorvastatin, but moderate with lovastatin and simvastatin (about 4-fold increase in statin levels). Limit lovastatin dose to 20mg and simvastatin to 10mg
  • Fenofibrate: insignificant interaction with all (though no data on lovastatin)
  • Gemfibrozil: minor interaction with atorvastatin and rosuvastatin. Avoid combo with lovastatin, pravastatin, and simvastatin
  • Verapamil: moderate interaction with lovastatin and simvastatin. Limit dose of lovastatin to 20mg and simvastatin to 10mg
  • Warfarin: 30% increase in INR with simvastatin, variable effects with lovastatin, rosuvastatin. But monitor INR with initiation or change in dose of any statin [which i think is reasonable with almost any new drug…]

A brief comment on cardiac and other drugs used less frequently in primary care:

  • Amiodarone: metabolized by both CYP34A and CYP2C8, as well as substrates of P-gp efflux transporter. Not use simvastatin (and definitely not more than 20mg) or lovastatin (not more than 40mg). rest are okay
  • Dronedarone: similar to amiodarone, but recommended to use simvastatin and lovastatin at even lower doses (e.g. not more than 10mg)
  • Ranolazine: best to use rosuvatatin, atorvastatin, pravastatin. FDA recommendation to limit dose of simvastatin to 20mg
  • Ticagrelor: can use atorvastatin; if use simvastatin or lovastatin, then no more than 40mg/d; no reported interactions with other statins
  • Conivaptan (a vasopressin receptor antagonist): not use lovastatin/simvastatin; best to use atorvastatin, pravastatin, or rosuvastatin. Tolvaptan can be used with any statin
  • Immunosuppressants: avoid combos of lovastatin or simvastatin with cyclosporine, everolimus, tacrolimus; best to use rosuvastatin up to 5mg, atorvastatin up to 10mg, pravastatin up to 20mg
  • Sacubitril/valsartan: limited data, minimal metabolism by CYP450 system, some increase in atorvastatin levels but no reported adverse clinical effects
  • Ivabradine: limited data, but extensively metabolized by CYP34A system (so, I would avoid simvastatin/lovastatin)


  • This review was helpful to me for a few drug-drug interactions in particular
    • Gemfibrozil: my prior held belief (and the 2013 American Heart Association guidelines statement) was that we should not use the combo of gemfibrozil with any statin, because of significant risk of myositis with the combo  (also some increased risk of hepatotoxicity). This created a bit of a problem, since studies do suggest that fenofibrate seems to be much less effective in lowering triglyceride levels and does not seem to have the same cardiovascular benefits of gemfibrozil (e.g., comparing the FIELD trial of fenofibrate and the VA-HIT or Helsinki trials with gemfibrozil; also a meta-analysis confirmed that fenofibrate is a poor cousin to gemfibrozil). These new guidelines still prefer using fenofibrate, since large studies with the statin/fenofibrate combo do not show an increased toxicity; and they suggest using atorvastatin or rosuvastatin at a lower dose (FDA suggests max rosuvastatin of 10mg/d) if use gemfibrozil. But at least the combo of gemfibrozil and atorvastatin or rosuvastatin is now acceptable.
    • It really is okay to use simvastatin with amlodipine, despite my electronic record and pharmacist yelling at me when I have tried to do so. Though, that being said, it does seem that atorvastatin is overall better tolerated in terms of drug-drug interactions (rosuvastatin and pravastatin are also quite good). The reason is that simvastatin and lovastatin are metabolized in the CYP3A4 system, the most common enzyme system in drug metabolism, and atorvastatin is metabolized by this system less so. Rosuvastatin is metabolized in the less commonly used CYP2C9 system. Pravastatin is not metabolized through the CYP450 system at all, but is by the OATP enzymes (organic anion-transporting polyprotein)
  • So, overall this guideline does present a more detailed (and complex) characterization of the drug-drug interactions between statins and other cardiac meds, and is pretty helpful with some very specific guidance. Unfortunately, it does not deal with non-cardiac meds (and, it turns out, that we in primary care do sometimes prescribe non-cardiac meds…)

Primary Care Corner with Geoffrey Modest MD: NSAID Use and Risk of Heart Failure

16 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent large case-control study confirming several other studies showing a significant risk of heart failure with the use of NSAIDs (see


  • Five large population health care databases from Europe, with 92,163 hospital admissions for heart failure, matched with 8,246,403 controls.
  • Mean age 77, 45% men, patients who developed heart failure were more likely to have history of cardiovascular disease (acute MI in 3.3 vs 1%, atrial fibrillation in 5.0 vs 1.3%, valvular heart disease in 2.6 vs 0.9%, hyperlipidemia in 20.4 vs 14.1%, diabetes in 19.4 vs 8.8%; and be on more meds (ACE/ARB in 42.1 vs 24.6%, b-blockers in 24.4 vs 15.2%, diuretics in 53.2 vs 18.6%)


  • Current use of any NSAID in the preceding 14 days (vs past use greater than 183 days in the past) was associated with a 19% increase of hospital admission for heart failure with OR 1.19 (1.17 to 1.22)
  • In terms of specific NSAIDs, odds ratios of first admissions for heart failure:
    • ketorolac: OR 1.94 (1.71 – 2.19)
    • indomethacin: OR 1.52 (1.31 – 1.77)
    • diclofenac: OR 1.21 (1.16 – 1.26)
    • ibuprofen: OR 1.15 (1.08 – 1.21)
    • naproxen: OR 1.19 (1.08 – 1.31)
    • nabumetone: OR 1.07 (0.81 – 1.43), nonsignificant
    • celecoxib: OR 0.95 (0.89 – 1.02), nonsignificant
  • Almost all of these associations were more profound in those with prior history of heart failure admissions (most extreme was for ketorolac, which developed an OR of 5.09; though the association with naproxen and diclofenac became nonsignificant in those with prior history)
  • There were pretty evident dose-response curves, with the higher doses of NSAIDs associated with more heart failure for many of the NSAIDs. This was measured using Daily Dose Equivalents (DDD), which is the “average maintenance dose”, not specifically defined for each NSAID, but they found the following, with medium dose being 0.9-1.2 DDD, high 1.3-1.9, and very high (>=2): [note: there were only 2 databases which provided this info, and the numbers of people in some of the categories was small]
    • Diclofenac went from insignificant increase in heart failure at low to medium dose, then to OR 1.1 for high and 2.2 for very high
    • Indomethacin increased with increasing dose (p<0.001) for the trend, with OR 1.7 for medium and high dose, jumping to 2.5 for very high, but too wide a confidence interval to make it significant
    • Naproxen OR 1.3 for high and 1.4 for very high
    • Not a clear trend (the very high DDD had OR 1.9, but very wide confidence intervals)
    • Celecoxib: no trend


  • This study basically confirms that NSAIDs are associated with heart failure, and that some are better than others (though I should add that those who developed heart failure were sicker and had more co-morbidities that would make heart failure more likely, even though there were attempts to mathematically control for that). Of note, this study and some others have found that celecoxib (as opposed to pretty much any of the other COX-2 inhibitors) seems to be better [and other studies have found that it does not seem to provoke MIs as does rofecoxib/Vioxx]
  • Most of the above associations applied to men and women, though were stronger in men
  • The dose response curve found with several of the meds (higher dose with more heart failure) serves to reinforce the likely causality of the association
  • The likely mechanisms are related to inhibition of prostaglandin synthesis, which leads to increased peripheral resistance (and blood pressure, another important adverse effect), decreased renal perfusion/GFR (and renal dysfunction, yet another), and decreased sodium excretion/sodium retention
  • As many of you know, I am very concerned about long-term use of NSAIDs and PPIs, in part because they are used so frequently (and are available OTC, which also creates the impression that they must be safe) and because of their litany of significant adverse events (for some of my previous blogs on NSAIDs, see links below). And, of course, the reason they are used so much is because they are really effective. Which makes our tasks harder: how to convince patients to use less toxic meds
    • By downgrading NSAIDs, preferably to nonpharmacologic therapies such as PT or yoga; or through local injections, often given once or infrequently, which do spare systemic side effects in general
    • And downgrading PPIs to H2-blockers or calcium antacids along with sometimes helpful dietary changes

See for FDA warning about NSAIDs and increased risk of heart attack or stroke

See for blog on the role of H pylori in increasing the risk of GI bleeds in those on NSAIDs

See for increased risk of afib with NSAIDs

Primary Care Corner with Geoffrey Modest MD: HIV Drug Costs and Effectiveness. Are We Going in the Wrong Direction?

8 Nov, 16 | by EBM

By Dr. Geoffrey Modest

An observational cohort study looked at patients on antiretroviral therapy (ART) for HIV, finding that some of the most effective yet cheapest regimens are not being recommended for use today (see Eaton EF. AIDS 2016; 30: 2215). I have included the 340b pharmacy pricing, which is the reduced federal pricing available since 1992 to eligible health care organizations (mostly Federally-funded clinics and public hospitals) vs the AWP, average wholesale price, used in private pharmacies.


  • 491 patients (mean age 36, 83% men, 61% African-American) initiating anti-retroviral therapy (ART) between 2007-2013, at the University of Alabama at Birmingham
  • Durability (time from regimen initiation to discontinuation), used as a surrogate for the combo of effectiveness and tolerability.
  • Results for the 5 most common ART regimens used during that time:
    • TDF/FTC (tenofovir disoproxil fumarate/emtricitabine) with efavirenz (atripla): durability 40.1 months; 340b price $726.26
    • TDF/FTC with raltegravir: durability 47.8 months (longest); 340b price $1080.60
    • TDF/FTC with darunavir/ritonavir: durability 47.8 months (longest); 340b price $1153.00
    • TDF/FTC with atazanavir/ritonavir: durability 31.9 months (shortest); 340b price $1070.88
    • TDF/FTC with rilpivirine: durability 3 months; 340b price $917.50
  • Overall, combining durability with price, the efavirenz (atripla) regimen dominated, with the rilpivirine one following closely behind


  • Several of the older treatments have been downgraded in recent guidelines, including atripla (TDF/FTC/EFV) for neuropsych effects of dizziness, anxiety, lack of concentration, vivid dreams and suicidality (though large observational studies have not found increased suicidality) and complera (TDF/FTC/rilpivirine) since it is less effective in those with high HIV viral loads.
  • The new guidelines do attach a comment that we should consider cost in determining the regimen, but they formally downgraded the cheapest regimens. For a review of the guidelines, see for the Intl Antiviral Society–USA guidelines, or go to for the DHHS updated guidelines (these 2 do differ slightly, with the first one suggesting the TAF (tenofovir alafenamide) regimens only, but the first-line regimens are basically the most expensive of the list below)
  • I did get today’s 340b pharmacy costs for common HIV meds, for a 30-day supply (note: the 340b cost is much lower and does not track well with the AWP)
    • Atripla (TDF/FTC/EFV): $688.93 (generic is still not available, but should be soon, which should drive down this cost)
    • Truvada (TDF/FTC): $428.61 (generic is still not available, but should be soon, which should drive down this cost)
    • Raltegravir: $591.58
    • Descovy (TAF/FTC): $428.61 (ie, same price as brand-name truvada, and probably because the drug company wants us to continue with this product instead of the switching to the generic truvada when available. And though TAF does not have the long clinical trials of TDF, it does offer some real potential advantages in terms of decreasing the renal and bone toxicities of TDF)
    • Tivicay (dolutegravir): $832.44
    • Odefsey (TAF/FTC/rilpivirine): $1716.13
    • Genvoya (elvitegravir/cobicistat/TAF/FTC): $1893.68
    • Stribild (elvitegravir/cobicistat/TDF/FTC): $1638.87 (though here, substituting TAF for TDF does seem to increase the cost….)
    • Prezcobix (darunivir/cobicistat): $759.39
    • Evotaz (atazanavir/cobicistat): $700.70
    • Triumeq (dolutegravir/abacavir/3TC): $1580.35
  • Just to put all of this in perspective:
    • The new drugs are really great, with excellent acceptability (I have had to stop dolutegravir only once for GI effects), along with remarkable efficacy, combined with much more “leniency” than the older drugs such as efavirenz (one can miss more doses but maintain continued viral suppression, without developing resistance so easily)
    • But the old drugs (especially atripla) were the ones which were able to turn the AIDS from almost uniformly fatal to almost uniformly a chronic disease
    • And, the vast majority of patients tolerated these drugs well. The +/- 90%  who were able to continue on them had the same remarkable great outcomes as with the new drugs (I have rarely had to change my old patients on atripla to one of the newer formulations)
    • And, these old regimens are likely to get much cheaper when generics become available
  • So, what does this all mean? We live in an extremely expensive health care system (1/3 of Massachusetts spending is for healthcare/Medicaid), yet we have the remarkably opaque system where clinicians providing the care are “shielded” from its cost. Hospitals do not provide us with the cost of MRIs or colonoscopies, or the fact that at one hospital it is 2-3x the price of another. It is not easy to find the actual costs of medications, and this cost can vary considerably from one pharmacy to another (again, it is a lot of work for us to find out the actual costs). Drug companies and hospitals, in these cases, have no interest in advertising costs — drug companies promote the “newest and best” to us through sponsoring the studies and advertising aggressively (and expensively) to us and directly to consumers, highlighting their new cancer drug which increases life expectancy a couple of months at $100,000 per injection, etc etc. Ironically, we clinicians as consumers would (mostly, I assume) never tolerate buying other consumer products without knowing their price and their relative value compared to other items of the same class. so, though I have been prescribing these new HIV drugs to my newly diagnosed patients, I think this article really does give pause and highlights the strange situation we are in in our increasingly expensive, increasingly unaffordable, intentionally cost-opaque health care system, which in many ways does not lead to major improvements in community health or health care outcomes, yet with us as clinicians inadvertently being put in the position of how $$ is spent: a perfectly devised system to maximize the profits of the drug companies, hospitals, etc. And many of the people sitting on the committees writing the new guidelines in medicine are financially supported by drug companies, etc, both for their research and personal financial gain, which really should be seen as an unacceptable conflict-of-interest.

See , a recent blog which includes reference to the book The Health Care Paradox, which argues well that we in the US spend huge amounts of money per capita on medical care but reap really poor-to-mediocre improvements in health outcomes (e.g., infant mortality or life expectancy being lower than almost any other industrialized country), because we devote the vast majority of the medical care $$ specifically to health care and such a low percentage to public health/social programs that promote the prerequisites for good health: good employment, housing, food, supportive social environments, exercise programs, day care/elder care……)

By Dr. Geoffrey Modest MD: AHA List of Meds to Avoid in Patients with Heart Failure

22 Jul, 16 | by EBM

By Dr. Geoffrey Modest

The American Heart Association has published a long article on medications which could cause or exacerbate heart failure (HF). For the complete text, see

  • HF is the leading hospital discharge diagnosis in patients >65yo. This group has a very high medication burden (given their age and the likelihood that they have multiple risk factors and medical comorbidities), and on average are on 6.8 medications/d with 10.1 doses/d, not including OTCs (over-the-counter meds) and CAMs (complementary and alternative meds). In one study, 88% of HF patients used OTCs and 35% herbal supplements/63% vitamins. These multiple meds expose patients to more adverse drug effects, exacerbated by the increased likelihood for drug-drug interactions
  • These are the commonly used primary care drugs listed in the article:
    • NSAIDs – pretty well-documented increases in HF precipitation and exacerbation, including both the nonselective and COX-2 inhibitors
    • Anesthetics and oncology drugs – will not comment much, since not such a primary care issue, but many can affect cardiac function or exacerbate heart failure (an array of direct cardiotoxins, as well as those that cause peripheral vasodilation, hypotension, increased sympathetic nervous system activity)
    • Metformin – initial concerns about lactic acidosis (a carry-over from phenformin, its no-longer-available relative associated with severe lactic acidosis and frequent deaths). BUT the FDA in 2006 removed HF as a contraindication for metformin, noting that in patients with HF, “the risk of metformin-associated lactic acidosis was minimal and similar to that of other diabetes mellitus medications in patients with HF and that metformin was associated with an overall reduction in mortality” (my emphasis). There is still some concern about using metformin in unstable HF patients or those hospitalized for HF, and they cite the 2016 Am Diabetes Assn guidelines as the source (for further analysis of this, see my commentary below).
    • TZDs and DPP-4 inhibitors for diabetes – reasonable data against using these meds in patients with HF
    • The array of antiarrhythmics with negative inotropy (flecainide, esp inthose with existing LV dysfunction; disopyramine; sotalol; dronedarone)
    • Antihypertensives:
      • Calcium channel blockers (diltiazem, verapamil, nifedipine). [The nifedipine issue is a little unclear to me: a small study (n=21) found worsening of HF. For its cousin amlodipine, an initial study actually found benefit for amlodipine in those with HF, however not replicated in a follow-up study, but there was no overall harm. There is more peripheral edema and pulmonary edema with both of these drugs, so I would be hesitant to use them acutely in patients with unstable HF, but for unclear reasons nifedipine but not amlodipine are on the AHA list. Not sure why the difference
      • a-blockers (prazosin, doxazosin): cause vascular smooth muscle relaxation and increased HF (e.g. ALLHAT trial)
      • Centrally-acting a-agonists: (clonidine). Small studies actually show some improvement in patients with HF, by decreasing sympathetic tone and improving hemodynamics, but the potential for bradycardia and AV dissociation are of concern
    • Selective a1-blockers (tamsulosin, etc.): seem to be associated with increased HF hospitalizations, esp if not getting concomitant b-blockers (suggesting unopposed a1 stimulation could lead to b1-receptor stimulation, with increases in renin/aldo, and edema). No clear data that there are HF exacerbations, but still a concern and should be used cautiously
    • Itraconazole, though terbenifine also has liver toxicity but is not associated with HF and is not on the list
    • Albuterol (from decreased b-receptor responsiveness with continued use)
    • Cilostazol: associated with increased heart rate, PVCs/nonsustained ventric tach, though no data showing increased risk of arrhythmias in those with HF. But best to avoid
    • Stimulants (amphetamines, etc.): increase blood pressure, reports of sudden death, acute coronary syndromes, MI, etc. But large epidemiological studies do not confirm excess of serious cardiovasc events
    • Anti-epileptics: carbamazepine is associated severe LV dysfunction seen clinically only with overdoses, though there is potential for hypotension, bradycardia, AV block; pregabalin is associated with peripheral edema, perhaps from direct vascular effects and not from HF (as with dihydropyridine calcium channel blockers) though some HF case reports
    • Antipsychotics: both typical and atypical are associated with sudden cardiac death, arrhythmias, prolonged QTc intervals, tachycardia and hypotension
    • Antidepressants:
      • Tricylcic antiderpressants are associated with tachycardia, postural hypotension, AV conduction, increased QTc, and can be associated with cardiomyopathies.
      • Citalopram is associated with increased QTc, though very rare case reports of torsades, and hard to disentangle the many other meds being taken by patients in these case reports that could also cause torsades. Also, the limited case report data suggest no citalopram dose-relationship
    • Anti-parkinsons meds: valvular regurgitation with pergolide or cabergoline. Limited similar data on bromocriptine. But large epidemiological studies did not find much harm
    • Bipolar meds: lithium is associated with bradyarrhythmias, PVCs, AV block, T-wave depression, cardiomyopathy.
    • Hydroxychloroquine: 70 cases of cardiotoxicity
    • OTC meds: a few of the bad actors above (e.g. NSAIDs) are available OTC, along with vasoconstrictors (phenylephrine/pseudephedrine) which can cause cardiotoxicity, sympathomimetics (asthma meds), and many OTCs are formulated with lots of sodium (cough/cold meds, gaviscon)
    • CAMs: some of clear concern (ma-haung, an ephedra-like product which can cause increased blood pressure and heart rate), even vitamin E >= 400IU has been associated with HF. Some CAMs have significant interactions with cardiovasc meds used for HF (especially grapefruit juice, St. John’s wort, black cohosh). The major concern is the lack of studies showing the safety of the vast majority of CAMS


  • My concerns:
    • They lump together clear cardiotoxins, with documented meds which lead indirectly to HF exacerbations (NSAIDs), with really beneficial meds with little data suggesting adverse HF effects (e.g. metformin). Though they do defend their list by citing important studies, and they duly note that there are differing levels of HF concern, I fear that when the lists are published and widely spread, these major differences may be blurred over and may lead to fear of using important and helpful meds. And many of the above AHA concerns are based more on theoretical issues and not hard data (e.g. carbamazepine).
    • In terms of their listing metformin:
      • There are pretty impressive small studies showing benefit for metformin in those with HF. But the AHA listed that it was potentially a cause of problems (lactic acidosis) especially in those with unstable or hospitalized with HF. They cite the ADA recommendations, which cite a 2013 comparative safety and effectiveness study (see Eurich D. Circ Heart Fail. 2013; 6: 395), which not only did not cite any data on metformin use in such patients (and did not recommend against metformin use in these patients), but notes no increased risk of lactic acidosis overall and that metformin was associated with a small reduction in all-cause hospitalizations in those with HF (including those with LVEF <30%) and chronic kidney disease!!!
      • There are animal data suggesting that metformin improves cardiac function (decreases oxidative stress, improves insulin resistance, prevents progression of HF, improves cardiac structure/function/survival, attenuates LV remodeling and improves cardiac mechanical efficiency….)
      • And, in their assessment of the “Magnitude of HF induction or precipitation” they classify of metformin as being a “major” risk with the possible mechanism being “lactic acidosis”, which seems to me to be pretty unwarranted. especially since the studies overall and the FDA do not support an increase in lactic acidosis
    • But, this brings up an issue in medicine: carrying over information which may be distorted in one paper (the ADA recommendations), though on looking at the actual source, there was no such data or conclusion. I definitely see articles where the abstract distorts the conclusions from the actual study and, as above, where the supporting references for a statement in fact do not support the statement. I think this is less frequent now than several decades ago, but is still an issue (as in this metformin case)
  • So, bottom line: I am concerned that this list could be used indiscriminately to avoid using important drugs, even though the different drugs are noted to have markedly differing levels of potential problems. Clearly there is a difference between drugs directly related to clinical HF and those with potential mechanisms but little clinical data. And I would add that there is a real difference between some very important drugs clinically (e.g. nifedipine/amlodipine, where the importance of lowering blood pressure and the attendant clinical benefits may far outweigh the potential adverse effects), and those drugs which either have not a huge clinical impact or there are safer alternatives (e.g., for onychomycosis, I do not use itraconazole anymore, mostly terbenafine; or citalopram, where there are no good clinical data that these really are bad, but there are so many alternatives that can be used, such as sertraline). And, even in terms of metformin (my biggest concern in this AHA list), I personally would still be careful using it in patients with unstable HF, since there is not much of an upside (no real harm in waiting a short time when the patient is unstable, though I would use it at low dose in those who are chronically unstable and with okay renal function, see blog below) and there is the potential (though not well-documented) downside of lactic acidosis. However, if the drug is on the above list, it certainly does make sense to watch these patients a bit more closely.

For more blogs on metformin, see , which includes the revised and much more lenient FDA recommendations on metformin use in those with kidney disease, as well as other blogs (showing, for example, that metformin induces changes in the microbiome leading to decreased insulin resistance).

Primary Care Corner with Geoffrey Modest MD: FDA Warnings Fluoroquinolones, Aripiprazole, Olanzapine

31 May, 16 | by EBM

By Dr. Geoffrey Modest

The FDA has sent out several Drug Safety warnings in the past few weeks.

  1. Fluoroquinolones
  • Given the widespread reports of adverse effects of fluoroquinolones, the FDA issued a report in 2013 requiring a label change (see ). Specifically, they noted an association with disabling peripheral neuropathy (with the onset of peripheral neuropathy often within a few days of starting the fluoroquinolone, and ongoing symptoms for more than a year in some patients, long after stopping the med).
  • There already were labels warning about risks of tendinitis, tendon rupture, CNS effects, exacerbations of myasthenia gravis, QTc prolongation/torsades, phototoxicity, and hypersensitivity (and I did send one patient to the ICU with anaphylaxis from ciprofloxacin around 15 years ago)
  • The actual warning from 5/12/16 states that the FDA “is advising that the serious side effects associated with fluoroquinolone antibacterial drugs generally outweigh the benefits for patients with sinusitis, bronchitis, and uncomplicated urinary tract infections who have other treatment options”. See .
  1. Aripiprazole
  • The FDA just issued a safety alert for aripiprazole (goes by trade name Abilify). See This medication has FDA approved indications for treating schizophrenia, bipolar disorder, Tourette’s disorder, and irritability associated with autistic disorder. It is also used (and apparently advertised widely on TV) in combination with antidepressants to treat depression. The FDA is warning that it might be associated with compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex. And these urges desist on stopping the drug or with dose reduction. But 4 cases had a return to this behavior with rechallenge. They do note that these impulse-control problems are rare (184 case reports since 2002, though there are apparently 1.6 million patients on the drug), with pathological gambling being the most common. The recommendation is just that we and patients be alert to this possibility. And we should closely monitor patients at higher risk for impulse-control problems, including personal/family history of obsessive-compulsive disorder, impulse-control disorder, bipolar disorder, impulsive personality, alcoholism, drug abuse, or other addictive behaviors. But in most cases there was no prior history of compulsive behaviors overall, and none had a history of pathological gambling, compulsive sexual behavior, binge eating, or compulsive shopping prior to taking aripiprazole.
  • On reading about aripiprazole it is quite remarkable the array/diversity of actions it has: (per com) — “Aripiprazole exhibits high affinity for dopamine D2and D3, serotonin 5-HT1A and 5-HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors, and moderate affinity for the serotonin reuptake site. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.]” It is certainly true that many CNS-active drugs have multiple effects on multiple neurotransmitters, leading to many of their attendant adverse effects, though aripiprazole outdoes seem to outdo some of the others.
  1. Olanzapine
  • The FDA issued a drug safety communication about olanzapine and DRESS syndrome (see ).
  • DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) often starts as a rash that spreads to all parts of the body, and includes 3 or more of: rash, eosinophilia, fever, lymphadenopathy, and systemic complications (hepatitis, myocarditis, pericarditis, nephritis, pancreatitis, pneumonitis), and often occurs after a long latency of 2-8 weeks after drug exposure. there is a 10% mortality rate
  • 23 cases of DRESS have been reported since 1996. One patient has died.


So, as with all FDA reports, these cases likely significantly underestimate the true incidence of problems, since in a busy clinical session, it is difficult/time-consuming to report the adverse events. But it is important for us as clinicians to know about these potential issues. The most important one for us is the fluoroquinolone advisory. As many blogs and articles have articulated: many too many antibiotics are being used for non-bacterial infections (bronchitis, sinusitis…), and there has been a very unfortunate shift to using more broad-spectrum and resistance-producing antibiotics (more azithromycin for strep, etc., than narrower antibiotics like penicillin). And I think many of us do still use ciprofloxacin for uncomplicated urinary tract infections.

See for studies on antibiotic overprescribing and their consequences

Primary Care Corner with Geoffrey Modest MD: PPIs and Chronic Kidney Disease

15 Jan, 16 | by EBM

By Dr. Geoffrey Modest

An article just came out looking at the relationship between PPI (proton-pump inhibitor) use and chronic kidney disease (CKD) (see doi:10.1001/jamainternmed.2015.7193).


  • 10,482 patients in the ARIC study (Atherosclerosis Risk In Communities, in 4 US communities) who had baseline GFR of >60 ml/min/1.73 m2 in 1996-9 were followed until 2011, mean 13.9 years
    • Mean age 63, 44% male, 80% white, 80% with education >=12th grade, mean eGFR 88, urinary albumin/creatinine ratio 4, 12% smokers, BMI 29, systolic BP 127, 50% hypertensive, 15% diabetic, 30% on NSAIDs, 15% on ACE inhibitors, 60% on aspirin
  • Replication study in the Geisinger Health System database with 248,751 patients followed mean of 6.2 years
    • Mean age 50, 43% male, 95% white, mean eGFR 95, 25% smokers, BMI 30, systolic BP 127, 33% hypertensive, 10% diabetic, 12% on NSAIDs, 30% on ACE inhibitors, 11% on aspirin
  • Assessed the occurrence of a diagnostic code for CKD in the ARIC study, and sustained GFR <60 in the Geisinger group, comparing PPI users, nonusers, and H2-blocker users


  • ARIC:
    • 56 incident CKD events among 322 baseline PPI users (14.2/1000 person-years) vs 1382 among 10,160 baseline nonusers (10.7/1000 person-years)
    • Unadjusted incidence of CKD in PPI users: HR 1.45 (1.11-1.90, p=0.006)
    • Adjusted for demographic (age, sex, race), socioeconomic (health insurance, education level) and clinical variables (baseline eGFR, urinary albumin/creatinine ratio, smoking, systolic BP, BMI, diabetes, cardiovasc disease, use of antihypertensives or anticoagulants): HR 1.50 (1.14-1.96, p=0.0013). They also considered annual household income, use of NSAIDs, aspirin, diuretics, statins, but these did not affect the adjusted HR results, so were not formally included.
    • Given that PPI use escalated dramatically after the baseline in years of 1996-9, they did an analysis of PPIs ever-used as a time-varying variable, with HR=1.35 (1.17-1.55, p<0.001)
    • In comparing PPI use vs H2-blocker use: HR 1.39 (1.01-1.91, p=0.05)  [Also, no association found between H2 blocker use vs non H2-blocker use and CKD]
    • In comparing PPI use to propensity-score matched non-users: HR 1.76 (1.13-2.74)
    • 10-year absolute risk of CKD among the 322 baseline PPI users was 11.8% vs 8.5% in nonusers
  • Geisinger:
    • 1921 incident CKD events among 16,900 baseline PPI users (20.1/1000 person-years), vs 28,226 events among 231,851 nonusers (18.3/1000 person-years)
    • Unadjusted incidence of CKD in PPI users: HR 1.20 (1.15-1.26, p<0.001)
    • For adjusted analysis HR 1.17 (1.12-1.23, p<0.001) (adjusted for age, sex, race, baseline eGFR, smoking, BMI, systolic BP, diabetes, history cardiovac disease, antihypertensive med use, anticoagulatnts, statins, aspirin and NSAIDs)
    • ​For time-varying ever-use model HR 1.22 (1.19-1.25, p<0.001)
    • Once-daily PPI use HR 1.15 (1.09-1.21, p<0.001)
    • Twice-daily PPI use HR 1.46 (1.28-1.67, p<0.001)
    • In comparing PPI use vs H2-blocker use: HR 1.29 (1.19-1.40, p<0.001=0.05) [again, no association between H2 blocker use vs non H2-blocker use and CKD)]
  • Also, the incidence of acute kidney injusry (AKI) was somewhat higher than CKD in both cohorts

So, a few points;

  • CKD is really common in the US (13.6% of adults, and increasing over time); not only is CKD associated with end-stage renal disease but also with increased risk of cardiovascular disease and death; there are clear relationships with many meds and CKD, an issue in the setting of increasing polypharmacy; PPIs are one of the most prescribed meds in the US (>15 million Americans had scripts in 2013) and are available OTC; they are increasingly prescribed to kids; and estimates are that 25-70% overall are not for appropriate indications, and that 25% of those on long-term PPIs could discontinue them without getting any symptoms.
  • This was a large observational study from 2 databases, with consistent results and even a dose-response relationship (at Geisinger, the more PPI taken, the more CKD). But, as an observational study, one cannot conclude that there is a causal relationship. Although mathematical attempts were made to control for many of the suspect variables (e.g., in the ARIC study, PPI users were more often white, obese and on antihypertensives), there still may be unknown or unaccounted variables (e.g., were those on twice-daily PPIs sicker in other ways which predispose them to CKD?, Does this modeling really apply to patients very under-represented in the cohort, such as non-whites?).
  • This study adds to the list of potential adverse effects associated with chronic PPIs: hip fracture, community-acqured pneumonia, c diff invections, acute interstitial nephritis, etc.
  • And, as mentioned in several prior blogs, the issue is that PPIs are often used as first-line therapy for gastritis or GERD (since they work so well, and not only make patients more reliably happier with their therapy but also give us a better diagnostic sense of what is going on), stepping-down therapy to an H2-blocker or antacid doesn’t happen often (much easier to continue the PPI and move on to dealing with the patient’s other concerns, easier to avoid a prolonged discussion and potentially ineffective move to the less powerful therapies…), and if the patient ever makes it to the ER or to a GI appointment, in my experience, they pretty much inevitably are given PPIs, often at maximal doses (which also makes it more difficult for the primary care provider to talk the patient into a less aggressive therapy). But, as mentioned in prior blogs and reinforced in the above study, although the short-term effectiveness of PPIs is pretty dramatic, they are really overused and the long-term sequelae may well be profound…

For other possible adverse events associated with PPI use, see

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