You don't need to be signed in to read BMJ Blogs, but you can register here to receive updates about other BMJ products and services via our site.


Primary Care Corner with Geoffrey Modest MD: PPIs and increased mortality

20 Jul, 17 | by gmodest

A large longitudinal study of US veterans found a 25% increased risk of death associated with proton pump inhibitor (PPI) usage (see 10.1136/ bmjopen-2016-015735)​.


— the researchers assessed three cohorts of patients, with 5.7 years of follow-up after the first acid suppression therapy prescription was written, and all patients had at least one outpatient serum creatinine value before acid suppression therapy was chosen:

— primary cohort: new users of PPI or H2 blockers (n=349,312)

— PPI versus no PPI users (n= 3,288,092)

— PPI versus no PPI and no H2 blocker (n= 2,887,030)

— covariates assessed included age, race, gender, renal function, number of outpatient serum creatinine measurements, number of hospitalizations, diabetes, hypertension, cardiovascular disease, peripheral arterial disease, cerebrovascular disease, chronic lung disease, cancer, hepatitis C, HIV, dementia, and diseases associated with acid suppression therapy for such GI conditions as GERD, upper GI bleeding, ulcer disease, H. pylori infection, Barrett’s esophagus, achalasia, stricture, esophageal adenocarcinoma.

— Analyzing the difference between the baseline demographics of these different groups: those on PPIs were older (eight months), and had more diabetes, hypertension, cardiovascular disease, and hyperlipidemia than the overall cohort, however looking at their numbers, these differences were on the order of 1% or less. The differences between those put on H2 blockers and PPIs was somewhat more significant, more typically on the order 5%.



— overall PPI use was associated with a 25% increased risk of death vs H2 blockers, HR 1.25 (1.23-1.28)

— using high dimensional propensity scoring (see below) there was a 16% increased risk, HR 1.16 (1.13-1.18)

— comparing PPI use to no PPI use, a 15% increased mortality risk, HR 1.15 (1.14-1.15)

— comparing PPI used to neither PPI nor H2 blockers, a 23% increased risk, HR 1.23 (1.22-1.24)

— in patients without underlying gastrointestinal conditions (those conditions being the ones noted above), those on PPI had 24% increased risk of death vs H2 blocker, HR 1.24 (1.21 1.27)

— among new PPI users, there was a graded association between the duration of exposure and the risk of death (all statistically significant, as compared to those who have taken PPIs <30 days): 5% increased mortality risk for those on PPIs 31-90 days, 17% for 91-180 days, 31% for 181-360 days, 51% for 361-720 days, all of these controlled for the array of comorbidities and risk factors above.



— the above analysis included both propensity scoring, a means to statistically equalize the PPI versus non-PPI users for all of the covariates above, as well as high dimensional propensity scoring, which controlled for an additional potential 500 variables to further minimize confounding

— a recent blog reviewed the risks and benefits of PPIs from the perspective of the American Gastroenterological Association, assessing the literature on the PPI association with kidney disease, dementia, bone fractures, small intestinal bacterial overgrowth, non-typhoidal Salmonella, Campylobacter, spontaneous bacterial peritonitis, C. difficile, pneumonia, calcium/iron/magnesium deficiency, B12 deficiency, and GI malignancies.

— There is also emerging in vitro evidence that PPIs can result in inhibition of lysosomal acidification and impairment of proteostasis, potentially increasing oxidative stress, endothelial dysfunction, telomere shortening, and accelerated human endothelial senescence. In addition animal studies suggest that PPIs decrease the regenerative capacity of livers following partial hepatectomy.

— This VA study, as well as these others reviewed by the AGA, is an observational one. For observational studies, the increased risk found is on the lower side to be significant. The impressive aspects of the study include the fact that it is huge, that they have controlled for a lot of variables (though they do not have specific data on obesity, smoking, and the use of specific medications including anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatories); that the risk was independent of prior GI symptoms, and that there was a clear dose-response curve (and the 51% increase in those on PPIs for >1 year is getting more impressive). In addition, looking at survival curves for those on PPIs versus H2 blockers, the difference increases linearly over time (ie the curves are splaying apart)


— As mentioned in previous blogs, PPIs are significantly overprescribed, in part exacerbated by their availability over the counter, with studies suggesting that 53-69% are used for inappropriate indications, that the risks of PPIs are poorly understood by patients as well as perhaps some clinicians, that many patients even with severe GI symptoms respond well to H2 blockers or antacids, and that it is often difficult for an array reasons for clinicians and patients to step down therapy to H2 blockers or antacids (e.g., clinicians having relatively limited time with patients are more likely to discuss other pressing medical or psychosocial problems as opposed to spending time trying to convince a patient to step down their therapy; and patients may well be so satisfied with the effectiveness of the PPI, perhaps prescribed by a specialist which might sway them more towards taking the PPI, that they are reluctant to give H2 blockers or antacids a fair trial).

–In my experience with many patients on PPIs, often they self-titrate to use them intermittently, but in any event are usually quite willing to try H2 blockers or antacids when I express my concern about the potential long-term problems by continuing to take such a potent drug when usually a less potent and possibly less harmful one often works as well.


Primary Care Corner with Geoffrey Modest MD: Dyspepsia guidelines

18 Jul, 17 | by gmodest

by Dr Geoffrey Modest

​​The American College Of Gastroenterology and the Canadian Association of Gastroenterology updated their guidelines on the management of dyspepsia (see doi: 10.1038/ajg.2017.154​)


Recommendations (note: the recommendation is much weaker when they use the word “suggest” vs “recommend”):

— they suggest endoscopy for dyspepsia patients greater than 60 years old: conditional recommendation/very low-quality evidence. they raised the age from 55 of prior guidelines since the age-specific incidence of gastric cancer has fallen in the US, and they feel the cost of endoscopy per case of cancer detected is prohibitive. they also do suggest this guideline be individualized, so that for patients coming from areas with high upper GI malignancy rates there should be a lower threshold for endoscopy, especially those coming from Southeast Asia and some countries in South America.

— they suggest not to do endoscopy to investigate alarm features (e.g. weight loss, anemia, dysphagia, persistent vomiting) for dyspepsia patients under the age of 60 . This recommendation is based on seven studies finding that alarm features had limited value for detecting any organic pathology: conditional recommendation/moderate quality evidence

— they recommend that dyspepsia patients under the age 60 should have a noninvasive test for H. pylori, with therapy if positive: Strong recommendation/high quality evidence

— they recommend that dyspepsia patients under the age of 60 should have empiric PPI therapy if they are H. pylori negative or remain symptomatic after H. pylori eradication therapy: Strong recommendation/high quality evidence

— they suggest dyspepsia patients under the age of 60 not responding to PPI or H. pylori eradication therapy should be offered prokinetic therapy: Conditional recommendation/very low- quality of evidence.  Metoclopromide should be given for less than 12 weeks [a problem given the chronicity of dyspepsia, but this drug does have significant adverse effects such as tardive dyskinesia], and domperidone dose should be 30 mg a day or less (this medication is not available in the US).

— the recommendations for patients with functional dyspepsia mirror the above, except that those patients who fail PPI or H. pylori eradication therapy should be offered tricyclic antidepressant therapy (Conditional recommendation, moderate quality evidence), and that those not responding to any of these be offered prokinetic therapy (conditional recommendation, very low-quality evidence). Those with functional dyspepsia not responding to any drug therapy should be offered psychological therapy (conditional recommendation, very low-quality of evidence.) They do not recommend the use of complementary or alternative medicines or the routine use of motility studies, except when gastroparesis is strongly suspected (several studies have found that the relationship between dyspeptic symptoms and gastric emptying is poor). The basis of their recommendation for tricyclics is that there were 3 studies looking at patients with functional dyspepsia finding a significant effect in reducing dyspepsia symptoms. No effect has been seen with SSRIs.



— as we all know, dyspepsia is quite prevalent, approximately 20% of the population globally. More common in women, smokers, and those on NSAIDs. The cost to the US healthcare services is over for $18 billion a year, societal costs are likely double that from time away from work.

— The definitions they are using:

— dyspepsia: predominant epigastric pain lasting at least one month, can be associated with epigastric fullness, nausea, vomiting, or heartburn, provided that epigastric pain is the patient’s primary concern (they are trying to minimize the inclusion of GERD in this category)

— functional dyspepsia: patients with dyspepsia where endoscopy and other relevant tests have ruled out organic pathology that explains the symptoms


So, a few comments:

— there are a few items above which counter conventional approaches, including not doing endoscopy to investigate alarm features in those <60 years old (they do comment that studies do not suggest that the predictive value of alarm features is very good, though the quality of evidence to support this is very low)

— I personally think the flow of the above algorithm is somewhat flawed. Those either with functional dyspepsia or plain old dyspepsia who have significant life stressors or other psychosocial conditions should be appropriately treated for those, usually at the same time acid suppression therapy is used, instead of the old biomedical approach, reiterated above, that one tries to treat all medical problems first and if all else fails treat the psychological problems. There have been studies in the past which have shown, not surprisingly to those of us in clinical practice, that stress can produce dyspepsia, with other old studies also showing an increase in gastric acid production.

— The above recommendations apply to symptomatic patients and strongly recommend treating H Pylori infections. As mentioned in many prior blogs, I tend to be quite aggressive in diagnosing and treating H. pylori infections, even if asymptomatic, because of the association with gastric cancer. This is reinforced to me because I treat a population with a very high prevalence of H. pylori, and what seems to me a high incidence of gastric cancer (which in fact is prevalent in the countries from which they hail). See blog reference below.

— another issue is the potential problems with the long-term use of PPI therapy. As commented previously, many patients have been put on PPIs for inappropriate indications (and they are available OTC, to boot). Many dyspepsia patients do respond to H2 blockers or even calcium antacids, which do not put them at higher risk of the many possible complications of long-term PPIs (a blog will come out soon on the association of PPIs with increased overall mortality). In fact, in seven RCTs involving 2456 dyspepsia patients, there was no statistically significant difference between PPI and H2 blocker use in providing symptom relief. And, patients initially treated with PPIs very often can be stepped down to H2 blockers or antacids, though many of these patients do well with stepped down therapy​.



blog for a summary of risks and benefits of PPIs

blog  for a summary of the H Pylori treatment regimens

blog  for a review of H pylori eradication and decreases in gastric cancer

Primary Care Corner with Geoffrey Modest MD: Benzos may not increase mortality risk

17 Jul, 17 | by gmodest

by Dr Geoffrey Modest

​ The BMJ just had an article assessing mortality from benzodiazepines from a large US commercial healthcare database, showing minimal increased mortality risk (see


— 1,252,988 randomly selected patients, comparing those initiated on a benzodiazepine during a medical visit within the prior 14 days vs 1,252,988 non-initiators, from 2004-2013

— all patients were required to fill at least one prescription for any medication both in the 90 days and 91- 180 days before the index date (ie, they were plugged into medical care and filling prescriptions), and high dimensional propensity scoring was done (see below).

— Mean age 46, 85% men, mean Charlson comorbidities score 0.5 (ie, low), 5% smokers, 4% obesity/overweight, 28% hypertension, 1% heart failure, 5% ischemic heart disease, 25% hyperlipidemia, 10% diabetes, 3% COPD, 5% asthma, 10% neuropathic pain, 20% back pain, 3% kidney disease, 10% cancer, 10% anxiety, 10% sleep disorder, 11% depression, 2% drug or alcohol misuse [reaffirming that this is a pretty healthy and younger population overall]

— Medications included SSRIs in 18%, opioids in 30%, barbiturates in 2%, antipsychotics in 2%, other anxiolytics in 1%

— of note, in comparing benzodiazepine initiators vs non-initiators, prior to propensity scoring, the benzodiazepine group had more smokers, hypertensives, atherosclerotic disease, hyperlipidemia, COPD/asthma, neuropathic pain, cancer, a lot more anxiety and depression, and were much more likely to be on beta blockers, steroids, opioids (35% vs 24%!!), anticonvulsants, SSRIs (22 vs 12%), and other hypnotics. All of these characteristics were well-balanced after propensity score matching

— Short acting benzodiazepines were more frequently prescribed, 75% of the filled prescriptions, and alprazolam was the most commonly prescribed of them (47.2%), and diazepam was the most commonly prescribed long-acting agent (87.8%). On review of their supplementary materials, they did include clonazepam as a short acting benzodiazepine, though it’s half-life is actually quite similar to that of diazepam  (both about 20 hours, sometimes much more: >60 hours)​. Not sure why they did that.

— main outcome: all-cause mortality, as determined by linking to the Social Security Administration Death Master File. The overall mean follow-up was 159 days for the benzodiazepine initiators and 146 days for the non-initiators.

— secondary analysis: comparing mortality in patients initiating benzodiazepines with other active treatments (i.e. SSRI antidepressants), also with high dimensional propensity score matching



— over 6 months of follow-up, there were 12.2 events per 1000 person-years in the benzodiazepine initiators vs 6.9 events per 1000 person-years non-initiators, a 78% increased mortality risk. But, given the different baseline characteristics of these groups, probably  the most relevant finding was that after the high dimensional propensity scoring, there were 5061 deaths in benzodiazepine initiators vs 4,691 in non-initiators, 9.3 vs 9.4 events per 1000 person-years; HR 1.00 (0.96 1.04 ). ie no difference

— a 4% increased mortality risk was observed in those on benzodiazepines when the observation period was extended to 12 and 48 months of follow-up.

— benzodiazepines were associated with a 9% increased risk as compared to those starting SSRIs

— in subgroup analysis, older patients initiating benzodiazepines with a longer half-life had no increased risk of all-cause mortality, however younger patients and patients using the short-acting benzodiazepines did have a 9% increased risk.


— Propensity match scoring was used to mathematically control for potential measured confounders. The high dimensional propensity score algorithm also used above is an automated technique which prioritizes/controls for more than 300 covariates that may serve as proxies for unmeasured confounders in large electronic databases. but it is important to reinforce that even large observational studies as this one do not enable us to draw definitive conclusions about causality: there still could be unmeasured variables which are primarily responsible for any associations. This population overall was pretty healthy, those on benzodiazepines less so, emphasizing that there might well have been other significant differences between these groups (though the lack of association is reassuring, since these sicker patients, controlling for their measured sicknesses but were probably at higher risk for other unidentified sicknesses and more likely to have a less healthy lifestyle, and they did not have higher mortality than the much less sick non-benzo initiators).

— As we know, benzodiazepines are frequently used in the outpatient setting, in 2008 approximately 5.2% of US adults aged 18 to 80 used benzodiazepines, increasing from 4.1% in 1996 to 5.6% in 2013. Similar numbers were found in British Columbia, Canada. Use increases with age, with a higher usage in those older than 50, especially for anxiety and sleep disorders. The concerns about their use in the elderly is related to prior reports of a threefold or more increased risk of all-cause mortality, even for short duration usage. And concerns remain about increased falls and fractures in the elderly. it should also be emphasized that this population above is a younger one, a selection bias related to the fact that this was a commercial healthcare database.

— It seems pretty remarkable that in the overall population, 35% of those who initiated benzodiazepines were on opioids vs 24% who did not start benzodiazepines. Given the apparent higher mortality of benzodiazepines in those on opioids found in a few observational studies (eg, see blog), it would have been useful to know specifically how the opioid subgroup fared. One concern that I have regarding the potentially increased mortality of combination of benzodiazepines and opioids is whether it is really from the combination or from the patient mortality associated with the conditions that the benzodiazepines might be treating (e.g. the significantly increased mortality of panic or other anxiety disorders).


—  the increases in mortality found in the subgroup analyses above were very small, though statistically significant because of the huge number of patients evaluated​. so, clinically they found essentially no difference in those initiating benzos

— from a clinical practice perspective, this study to me is largely reassuring​: I have certainly seen many older patients (again, not well represented above) who are severely functionally affected by anxiety, resistant to non-pharmacologic therapies as well as non-benzodiazepine drugs. I have prescribed benzodiazepines in many if them with excellent results. Preferentially I have used longer acting benzodiazepines, such as clonazepam (though as noted, they consider this a short acting benzodiazepine in the above study, but i think that might be an erratum), even in patients in their 90s. Patients certainly understand the potential increased risks of falls and possible increased mortality, but are desperate for immediate symptomatic relief.

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……)

EBM blog homepage

Evidence-Based Medicine blog

Analysis and discussion of developments in Evidence-Based Medicine Visit site

Creative Comms logo

Latest from Evidence-Based Medicine

Latest from EBM