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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 doi.org/10.1053/j.gastro.2017.01.031  ).

 

Details:

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.

 

BENEFITS:

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).

 

Commentary:

–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 Corner with Geoffrey Modest MD: PPIs and recurrent C diff infections

25 Apr, 17 | by gmodest

by Dr Geoffrey Modest

A recent systematic review and meta-analysis found that the use of protein pump inhibitors (PPIs) seems to be associated with increased recurrent Clostridium difficile infections (see doi:10.1001/jamainternmed.2017.0212)

Details:

— literature review from 1995 to 2015, specifically looking at case-control studies, cohort studies, and clinical trials, found 16 observational studies of 7703 patients with C. diff infections, 4038 (53%) were using gastric acid suppressants, and 1525 patients (20%) developed recurrent C. diff​ infections.

— These studies were performed in the United States, Korea, Israel, Europe, Japan, and Canada

— 9 studies involved PPIs alone, 5 with PPIs and H2 blockers, and one with H2 blockers alone.

Results:

— the recurrence rate for C. diff was:

–22.1% (892 of 4038 patients) in those taking gastric acid suppression

–17.3% (633 of 3665) in those not taking gastric acid suppression

an overall 38% increased risk, adjusting for age and potential confounders, OR 1.38 (1.08-1.76, p=0.02)

–subgroup analysis found that there was a 66% increased risk of C. diff recurrences with the use of PPIs, OR 1.66 (1.18-2.34), p=0.004, but not an increased risk in those they used both PPIs and H2 blockers, or H2 blockers alone (though only one study looked at H2 blockers by itself)

— the increased risk was found in both case-control studies and cohort studies

Commentary:

— Clostridium difficile infections are the most common cause of hospital-acquired diarrhea, and seem to be increasing in incidence, severity, morbidity, and mortality rates. At this point about 40% are community-acquired and in patients felt to be at low risk, suggesting that there may be new risk factors, including such things as gastric acid suppressants, C. difficile in the water and food, and close contacts with those with C. diff infections in the community.

— The studies are quite mixed on the relationship between gastric acid suppression and C. diff infections overall, especially when controlling for comorbid conditions and age. The connection seem to be somewhat stronger for PPIs versus H2 blockers, leading the FDA to issue a warning that PPIs are associated with an increased risk of C. diff infections (https://www.fda.gov/drugs/drugsafety/ucm290510.htm ).

— recurrent C. diff infections happen pretty frequently, as high as 50-60% after 3 or more infections. Risk factors for recurrence include older age, concomitant antibiotic use, and comorbid conditions. About 50% of patients with C. diff infections use concomitant gastric acid suppressants. Prior analyses have found an increased risk of reinfection in those on gastric acid suppressants, but these studies were limited by being retrospective or excluding important studies.

— The current study was methodologically more sophisticated, including prospective and retrospective case-control studies, as well as post hoc analysis of 2 RCTs

— gastric acid suppressants are known to alter the distal gut microbiota, with substantial decreases in bacterial diversity, and may make the microbiota more prone to both primary and recurrent C. diff infections. And data suggest that PPIs may affect the microbiota more than H2 blockers. On the other hand, the use of antibiotics to treat C. diff infections may further change the microbiota.

— these data are still observational, limiting our ability to attribute causality. For example, those on gastric acid suppressants are perhaps more likely to be elderly, using concomitant antibiotics, or having comorbid conditions which might increase the likelihood of C. diff infections. The authors did try to control for these issues, but this is difficult in a meta-analysis of 16 studies with different criteria and baseline data on patients.

see doi: 10.1038/ajg.2012.179, which presents a meta-analysis of 300,000 patients, finding a 65% increased risk of C diff  in patients on PPIs, independent of study design (case-control vs cohort), with the unusual p-value of “p<0.000”, which on the surface seems pretty strong…..)

see here for several prior blogs on C diff infections, including the use of probiotics and fecal transplants

see here ​ for a recent review of some of the benefits and harms of PPIs, including my concerns about their being overused in general, both by being overprescribed initially, and by continuing longterm instead of “stepping down” therapy.

The blog tomorrow will review a recent American Gastroenterological Association clinical practice update on the risks and benefits of PPIs.

Primary Care Corner with Geoffrey Modest MD: PPI Harms and Benefits

29 Aug, 16 | by EBM

By Dr. Geoffrey Modest

There was a useful editorial detailing the indications for long-term proton-pump inhibitor use (see Laine L. Am J Gastroenterol 2016; 111:913). As many of you know from prior blogs, I have been very concerned that many patients are on long-term PPIs because: they work; when patients are doing better on them, we can move on to address other issues; changing them involves somewhat detailed/time-consuming discussions with patients (detracting from focusing on the other issues); changing them may not work, so we might be back to square-one; when patients see GI specialists, they are uniformly put on PPIs (at least in my experience); and, despite GI specialty recommendations to step-down therapy from PPIs to H2-blockers or antacids, studies show that this rarely happens. This review focuses on the indications for long-term PPIs, with little attention to the harms, but my guess is that most patients on long-term PPIs do not qualify for them even by these recommended indications: there are some studies finding that 70-80% of hospitalized patients put on PPIs do not have an appropriate indication. Details of the editorial:

  • The caveat: most of the studies were intervention studies with retrospective observational analysis (i.e., they were not set up as large studies comparing different therapies, and following the patients for many years to assess long-term effectiveness or adverse events)
  • GERD: for GERD symptoms, most patients do well with on-demand therapy.  In general, advice is given for long-term PPIs if erosive esophagitis, and there are studies suggesting that there is a higher risk of recurrent erosion when patients are put on placebo, H2-blockers, or intermittent PPIs. BUT, there are no data that show that recurrent esophageal erosions are harmful or that not using daily PPIs leads to Barrrett’s, and the risk of strictures is really low. Of note, many patients do use PPIs intermittently for symptoms, no matter what clinicians suggest, and most do fine, and there are observational data finding benefit of intermittent 2-4 week courses of daily therapy if twice-weekly heartburn recurs. But, I certainly do have patients who continue with their daily PPIs even if not necessary… the FDA guidelines suggest 4-8 weeks of PPIs for GERD. The editorialists in this review suggest that patients taking PPIs for GERD stop therapy 2 weeks after symptom resolution, and use H2-blockers or antacids as needed for infrequent symptoms, and if necessary, intermittent PPI courses of 2-4 weeks when symptoms recur >= 2x/week. [Given that it is often hard to do step-down therapy for GERD symptoms, I usually start with H2-blockers, step up to PPIs if necessary, and then try to step-down. In patients with mild symptoms, antacids often work just fine]
  • Barrett’s: basically, observational studies suggest PPIs may decrease neoplastic progression of Barrett’s, but the Am College of Gastroenterology and Am Gastroenterological Assn guidelines are more cautious: stating that long-term PPIs should be “considered” or discussed carefully with patients. And absolute risk of Barrett’s progression to adenocarcinoma is low (0.1%/yr). No FDA approval for this indication. The editorialists prefer using daily PPIs only if necessary to control GERD symptoms.
  • NSAIDs (my other nemesis, in terms of overuse and a plethora of adverse effects: GI, cardiovasc, renal, etc): PPIs (or misoprostol) do seem to decrease GI bleeding in those at high risk of bleeding (>65yo, high-dose NSAIDs, prior ulcers, or concurrent steroids/anti-thrombotics), and is supported in RCTs. These editorialists feel this is a clear indication for PPIs, though FDA approval is for durations up to 3-6 months. [My approach overall is to avoid long-term or high-dose NSAIDs, preferring topical treatments such as local injections, capsaicin, lidocaine gel, diclofenac gel, or oral acetaminophen. And I do have very few patients who take NSAIDs other than very intermittently]
  • Aspirin/anti-platelet agents: guidelines recommend PPIs in those at increased risk of bleeding (history of ulcers, concomitant anti-thrombotics, age>60 plus steroid therapy). Endoscopic ulcerations and recurrent ulcer bleeding have been documented in RCTs. No FDA recommendation [I do have lots of patients on low dose aspirin for cardiovascular and colorectal cancer prevention. There are some studies suggesting that low dose enteric-coated aspirin is erratically absorbed, and that the non-enteric coated aspirin has no greater incidence of gastric ulcers, so that is the one I use routinely. And with really minimal GI distress. So I do not prescribe any gastric protection routinely]
  • Dyspepsia: PPI therapy if <55yo with uninvestigated dyspepsia who are H pylori negative, or if H pylori prevalence is <10%. RCTs suggest PPIs are more effective than H2-blockers or antacids, with NNT=5. No clear guidelines on this. I did look up the Am Gastro Assn guidelines and there were no clear therapies suggested (see http://gi.org/guideline/management-of-dyspepsia/ ). The editorialists suggest intermittent PPIs if effective to control symptoms [again, I have had considerable luck with H2-blockers or antacids, so I do try them first]

Commentary:

  • This editorial reviews the accepted recommendations for using PPIs, along with some of the available data. I think it is useful because so many of the patients we see in the community are on long-term PPIs for non-recommended indications.
  • And, there are substantial data in the literature on the potential adverse effects of PPIs, including the potential for gastric atrophy (a potentially premalignant lesion) especially in those with concurrent H Pylori infections, decreased mineral absorption (iron, calcium, magnesium), decreased vitamin B12, decreased bone mineral density and increased fractures, hypomagnesemia, increased enteric infections (C. difficile, C jejuni), increased pneumonia, and increased cardiovascular events. There have been more recent associations with chronic kidney disease and dementia (see blogs below).
  • And, in case you are interested, not so surprisinglyPPIs adversely affect the microbiome (after all, the acidity of the stomach probably does have some evolutionary protective effect on preventing enteric infections (and maybe much much more). see doi:10.1136/gutjnl-2015-310376 .
  • Of course, there are some patients who really do need PPIs for symptom relief/quality-of-life, but these can often be used intermittently.
  • So, I initially prescribe PPIs only in patients who have really severe presenting symptoms of GI distress (though I will often get a stool for H Pylori antigen prior to starting the PPIs). And in those already on PPIs I personally have had good success in switching people to H2-blockers, or even just intermittent antacids, though some do seem to need an occasional PPI, rarely daily long-term PPIs.

Prior blog on Barrett’s:

Relevant prior blogs on adverse effects of PPIs:

Primary Care Corner with Geoffrey Modest MD: Barretts Esophagus Guidelines

21 Jan, 16 | by EBM

By Dr. Geoffrey Modest

The American College of Gastroenterology updated their recommendations for screening for Barrett’s Esophagus (see doi: 10.1038/ajg.2015.322)

Background:

  • There is increasing prevalence of GERD in the US and worldwide
  • GERD is associated with 10-15% risk of Barrett’s esophagus (BE), i.e. in 1-2% of the population, with risk factors of male sex, central obesity, intensity/duration of GERD sx, and >50yo. The most profound risk factors are: those with early onset (<30 yo) and weekly symptoms (OR 31.4), and family history of BE or esophageal adenocarcinoma (EAC) (OR 12.23). White men with GERD have 2% chance of BE in the third decade of life, increasing to 9% by 6th decade. Men have twice the risk as compared to women for both BE and EAC. Alcohol does not increase risk of BE.
  • BE is associated with EAC, which has also been increasing in incidence. Risk factors for EAC in people with BE include: advancing age, increased length of BE segment, central obesity, tobacco use, lack of use of NSAIDs, lack of usage of PPIs, lack of usage of statins
  • The relationship with H pylori and BE is complex. Certain strains (e.g. cytotoxin-associated gene A, or Cag A+) may have a decreased risk. A VA study confirmed a lower risk of BE in those with H pylori, especially in those with gastric atrophy (which might be associated with the increased risk of stomach cancer, however) or use of antisecretory meds [see The American Journal of Gastroenterology109, 357-368 (March 2014)]. The Cag A+ strain is a more aggressive H pylori strain and decreases gastric acid production more, which may be the reason it may be somewhat protective for developing BE.
  • Risk of EAC:
    • For those without dysplasia, 0.2-0.5%/yr
    • With low-grade dysplasia: 0.7%/yr
    • With high-grade dysplasia: 7%/yr
    • ​90% of patients with BE die from causes other than EAC
      recommendations:
  • Consider in men with >5 year history and/or frequent (weekly or more) symptoms of GERD, and 2 or more risk factors (age >50, white, central obesity with waist circumf >102 cm/40 inches or waist-hip ratio of >0.9, current or past smoking, confirmed family history of BE or EAC in a first-degree relative. (Strong recommendation, mod level of evidence)
  • In females (who have half the BE risk), screening not recommended. But, consider in individual cases if multiple risk factors (as above, though in women waist circumf of > 88cm/35 inches or waist-hip ratio of >0.8). (Strong recommendation, low level of evidence)
  • Do not screen general population [though it is important to remember that 40% of EAC occur in patients without history of GERD]
  • Consider life expectancy in decision to screen
  • Can do unsedated transnasal endoscopy instead of conventional upper endoscopy
  • If initial endoscopy is negative for BE, no need to repeat. If esophagitis, repeat endoscopy after 8-12 weeks of PPI to ensure healing and exclude underlying BE (conditional recommendation, low level of evidence)

So, a few points:

  • The Am Cancer Society’s estimated incidence of esophageal cancer in 2015 is: 16980 new cases, with 13570 in men and 3410 in women.
  • Of the common esophageal cancers, BE is associated with adenocarcinoma and not with squamous cell carcinoma (squamous cell ca in Western countries is largely associated with alcohol and smoking, and its incidence is decreasing in parallel to decreases in these risk factors)
  • EAC has an abysmal survival rate when detected late (which is common in those who are symptomatic): those with regional or distant disease have a 5-year survival <20%.
  • I personally think there has been supportive data for many years that men >50yo with chronic GERD symptoms should get a one-time endoscopy, so I welcome that recommendation (and in the past, when I have referred patients for EGD, some gastroenterologists would do them and others would not). But there are some unclear parts of the new recommendations:
    • Per the letter of their recommendation, a 35 year old white man with central obesity and a 5.1 year history of GERD symptoms once a week should get an endoscopy. I doubt there are data to support that
    • ​Though women seem to be spared the higher likelihood of BE or EAC, EAC is still a terrible disease, so I would like to see a clear risk/benefit analysis before not recommending this screen. Prior guidelines from the Am Gastroenterology Assn have just focused on risk factors overall, where male sex is a risk factor, but women would be included in the recommendation for endoscopy if they had other of the risk factors.
    • One overhanging concern with the recommendations is the lack of smoking gun evidence that doing surveillance and treating Barrett’s leads to fewer cases of EAC. Case-control studies are suggestive (though there are some showing no decrease in cases in those undergoing consistent monitoring and treatment of BE), despite the reasonable pathophysiology suggesting an orderly progression from BE to increasing levels of dysplasia to malignancy.
    • Bottom line: who knows?? To make an informed decision, we need more data (e.g., does screening really work? What are the real risk/benefit analyses for women, assuming screening helps?). At this point, it seems reasonable to me to screen men and women with lots of risk factors one time around age 50 (though I understand that the number of people >50 yo who have central obesity, chronic GERD symptoms, and present/past cigarette smoking is pretty staggering).

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).

Details:

  • 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

Results:

  • 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

Primary Care Corner with Geoffrey Modest MD: Resume Anticoagulation After GI Bleed?

7 Jan, 16 | by EBM

By Dr. Geoffrey Modest

One of the many unanswered clinical questions is what to do with patients who have atrial fibrillation, are anticoagulated, but have a GI bleed. Do I just stop the anticoagulation? Should I bite my lip (but not too hard) and reinstate anticoagulation after the bleed? A recent observational study looked at this question, utilizing the great Danish clinical database (see BMJ 2015 Nov 16; 351:h5876​).

Details:

  • Danish cohort included all patients with atrial fibrillation (AF) from 1996-2012 who had a gastrointestinal (GI) bleed while on antithrombotic therapy. They then compared the patients who restarted therapy vs those who remained off therapy, beginning 90 days after the incident bleed
  • 4406 patients (mean age 78; 45% women; 24% on oral anticoagulation, 53% on antiplatelet agents, 19% on both; 25% on NSAIDs within 90 days of bleed, 15% on PPIs; 23% with prior stroke, 38% ischemic heart disease, 31% heart failure, 45% hypertensive, 20% vascular disease, 16% diabetic, 5% “alcohol misuse” as identified on admission for the GI bleed
  • Mean CHADS2 score of 2.1 (score of 1 means=moderate embolic risk, >=2 means mod-to-high risk), mean CHA2DS2-VASc score of 3.6 (score of >=2 means mod-to-high risk), mean HAS-BLED score of 2.6 (a composite of pro-bleeding factors such as hypertension, abnormal renal/liver function, labile INR, elderly, drugs/alcohol; where score >=3 means high risk of bleeding). Of note, there was really no difference in any of these scores in comparing those patients put back on oral anticoagulants or no meds. And no difference in whether they got gastroscopy or surgery, with 88% having gastric or duodenal ulcer, 12% gastritis, 2% GERD; and 5% with alcohol “misuse”, 90% on PPIs, 5% NSAIDs
  • 924 patients (27%) did not resume antithrombotic therapy (note: this is a large database study and not clear why the clinical decision was made to continue or stop therapy)

Results (I am only reporting results in those on single therapy with oral anticoagulant or antiplatelet agent):

  • In terms of absolute numbers, over a 2-year period, all-cause mortality of the whole group was really high at 40% (n=1745); thromboembolism was 12% (n=526); major bleeding was 17.7% (n=788) and recurrent GI bleed was 12.1% (n=546)
  • Comparing those who did not resume therapy with those who did:
    • For anticoagulant therapy (92% on vitamin-K antagonists):
      • All-cause mortality had HR=0.39 (0.34-0.46) – i.e. 61% reduction
      • Risk of thromboembolism had HR=0.41 (0.31-0.54) – i.e. 59% reduction
      • Risk of major bleed had HR=1.37 (1.06-1.77) – i.e. 37% increased risk, though a nonsignificant 22% increase in recurrent GI bleeds [HR=1.22(0.84-1.77)] perhaps because 90+% were on a PPI
    • For antiplatelet therapy (98% on aspirin):
      • All-cause mortality had HR=0.76 (0.68-0.86) – i.e. 24% reduction
      • Risk of thromboembolism had HR=0.76 (0.61-0.95) — also 24% reduction
      • Risk of major bleed (beginning 90 days after discharge from first bleed) had HR=1.25 (0.96-1.62 – i.e. nonsignificant 25% increased risk)
    • Subgroup analysis showed that as the CHA2DS2-VASc increased, there was associated decreased risk of all-cause mortality in those on anticoagulants (56% in those with CHA2DS2-VASc score of <2; 60% if 2-3; and 63% if >3); a HAS-BLED score >3 was associated with increased bleeding risk (41% if HAS-BLED score of <2; 64% if 2-3; and 57% if >3)
    • The single most effective change was taking patients who had been on an antithrombotic regimen (mostly aspirin) prior to the initial GI bleed and switching them to an oral anticoagulant (mostly vitamin K antagonist) after the bleed.

So, a few observations:

  • 25% of the patients with initial GI bleed were on NSAIDs. This is pretty clearly not a good thing, though hard to control completely given the easy availability of NSAIDs (I have had several patients on warfarin where I have explained the risk of NSAIDs, including naming the OTC brands, who subsequently used Advil or other OTC NSAIDs thinking they were okay. It probably is worth reiterating this message several times: by being OTC does not mean the drug is safe). Alcohol is another bleeding risk factor, which in those who drink excessively not only increases bleeding risk but also the risk of not taking anticoagulants correctly
  • I’m not sure what to make of the fact that many more of these patients were on antiplatelet agents (39% as single therapy) than anticoagulants (21% as single agents), given the high CHA2DS2-VASc scores overall (in general, the preferred therapy for those with CHA2DS2-VASc​ of 2 or more is oral anticoagulants)
  • Though they chose a waiting period of 90 days after the incident bleed to start their assessment of outcomes, there was no difference in sensitivity analysis if look at outcomes starting the day after the bleed
  • Although this was not a randomized controlled trial, there are several issues which I think make it still an important trial: this study involved a large number of patients drawn from a national registry which included all Danish residents and with linkage to pharmacy registries; there were minimal differences in the thrombotic risk (e.g. CHA2DS2-VASc score) or propensity to bleeding (HAS-BLED score) between the groups who resumed therapy and those not on therapy (i.e. no obvious selection bias); and there was a high absolute number of bad events overall and very high all-cause mortality benefit by reinstating anticoagulation. All of this suggests that there are reasonable grounds to restart oral anticoagulants, again with the proviso of trying to avoid NSAIDs and alcohol, and with close patient follow-up. Though it would be great to have a randomized controlled trial.

See http://blogs.bmj.com/ebm/category/cardiol-arrhythmia/ for many blogs on AF.

Also, another from the Danish registry looking at patients without AF but with heart failure and high CHA2DS2-VASc score, showing a high incidence of thromboembolism (see http://blogs.bmj.com/ebm/2015/09/24/primary-care-corner-with-geoffrey-modest-md-heart-failure-outcome-and-chads-vasc-risk-score-even-if-not-in-afib-2/ ).

Primary Care Corner with Geoffrey Modest MD: H. pylori and NSAIDs = increased GI bleeding

1 Jun, 15 | by EBM

By: Dr. Geoffrey Modest

A recent Spanish study looked at the risk of peptic ulcer bleeding in patients with H Pylori (HP) infection and in patients also using NSAIDs/low-dose aspirin (see Am J Gastroenterol 2015; 110:684–689). This case-control study looked at 666 patients with endoscopically-confirmed major peptic ulcer bleeding and 666 controls (matched by age, sex, month of admission), assessing medication use in the prior 7 days. HP was assessed by serology.

Results:

 –mean age 60; 29% female; with cases having significantly more smokers, ulcer history, dyspepsia, use of aspirin or NSAIDs, being on anticoagulants, not being on PPIs, and having HP infections (the latter being in 74.3% of cases and 54.8% of controls,  [RR: 2.6 (CI: 2.0-3.3)])

–aspirin use (<300 mg/d) was associated with 15.8% of cases vs 12% of controls [RR: 1.9 (CI: 1.3-2.7)].

–NSAID use was associated with 34.5% vs 13.4% of controls [RR: 4.0 (CI: 3.0-5.4)]

–aspirin use plus HP infection did not further increase the risk of bleeding  [RR:3.5 (CI: 2.0-6.1)]

–NSAID use plus HP infection did increase the risk of bleeding in at least an additive manner [RR: 8.0 (CI: 5.0-12.8)] 

–subgroup analysis of those on aspirin >500 mg/d found similar results to NSAIDs

–so, their conclusion: the risk of documented peptic ulcer bleeding was dramatically increased in those with H Pylori infection determined serologically who were on NSAIDs but not on low-dose aspirin

Here are a few older articles on this subject:

–the first I saw: a 1997 RCT in the Lancet looked at 202 patients with musculoskeletal pain who were going to be put on NSAIDs. These patients did not have prior NSAID exposure and did have endoscopically-documented but asymptomatic H Pylori infection. The researchers then assessed the incidence of GI bleeding in the group given H Pylori eradication meds vs those given placebo treatment, finding that the development of endoscopically-proven GI ulcers occurred in 26% of those with persistant HP and only 3% in those with HP eradicated (see Lancet 1997; 350: 975–79).

The American College of Gastroenterology published practice guidelines in 2009 which supported the conclusion that there is an additive role of H Pylori infection in those on NSAIDs in the development of ulcers and that 2 systematic reviews have shown that HP eradication is superior to placebo in preventing peptic ulcers among NSAID users.They comment that there is a potential advantage to H pylori testing and that then using either a gastroprotective agent or eradicating H Pylori may be useful depending on the individual’s underlying GI risk (see Am J Gastroenterol 2009; 104:728 – 738)​​

–also there have been several articles in my BMJ blog (for articles on treatment issues, see here. For an article on potential benefits in reducing gastric cancer, see here.)

So, what can one conclude?

–One could adopt the posture, as I do, that we should be screening and treating patients with HP more rigorously, with part of the rationale being that many people (perhaps, way too many) take a lot of NSAIDs and the data are pretty impressive that treating the HP infection decreases the risk of bleeding (though another angle is to gastroprotect everyone with a PPI, or possibly high-dose histamine-blocker — though I personally don’t fancy the idea of treating a potential complication of a med with another med, which in itself may have some adverse effects, such as osteoporosis, increased pneumonia, etc. I do very strongly try to limit use of NSAIDs in my patients as much as I can persuade them, given not just the GI effects, but effects on hypertension, heart failure, kidneys…  Also, as an aside and pretty anecdotal report: I saw a small clinical research study in the Lancet about 20-25 years ago showing dramatic resolution of ITP (idiopathic thrombocytopenic purpura) if one treats an underlying HP infection (in those infected). Then, about 2 weeks after seeing this, I had an Irish patient from Boston who had prednisone-resistant ITP, but (unexpectedly) had positive HP antibodies, got treatment for HP, and the ITP (with persistent platelet count in the 20,000 range and lots of ecchymoses) vanished and did not recur to date.

–The data on aspirin are reasonably consistent that there is not a clear additive effect with HP infection. One could still consider gastroprotection just because of the gastric effects of aspirin. I do reinforce with patients that low-dose aspirin is associated with GI bleeding, and that it is still prudent to avoid other GI irritants (smoking, alcohol, NSAIDs, etc). And, by the way, there are some concerns that enteric-coated aspirin may not be as effective for cardioprotection as regular 81mg aspirin and is no more gastroprotective.  See here for details.​

Primary Care Corner with Geoffrey Modest MD: Stress and peptic ulcers

1 Feb, 15 | by EBM

By: Dr. Geoffrey Modest

Older studies have shown an association between stress and peptic ulcer disease. At least the ones I’ve seen have not controlled for the use of NSAIDs or the presence of H pylori. However, from newer data, 16-31% of ulcers are not associated with either of these precipitating factors. The current prospective population-based study was done in Denmark, in which the researchers collected blood samples as well as an inventory of psychological, social, behavioral and medical data in 1982-3, and reinterviewed these patients in 1987-8 and 1993-4, finding that psychological stress did indeed increase the risk of ulcers (see doi.org/10.1016/j.cgh.2014.07.052​).

Details:
–3379 adults without prior history of ulcer disease were enrolled, with subsequent data on 2809 of them in 1987-8 and 2410 in 1993-4. Pretty evenly distributed in the 30-60 year age range.
–socioeconomic status (SES) was calculated from education, occupation, employment status. Stressors included working more than 40 hours/week and an assessment if the person had economic, work, family, housing , or personal problems. Subjects also answered 22 items from the Mental Vulnerability Scale (a questionnaire used by the military to screen potential recruits), a validated scale which assesses “somatization, neuroticism, depression, and anxiety.”
–a stress index was calculated which combined the baseline Mental Vulnerability; tranquilizer use; economic, work, family, housing or personal problems; unemployment; and working >40 hours/week — with a score of 0-10.​

Results:

–43% were H pylori positive, 16% were taking NSAIDs, 56% were current smokers, 39% in the lower two SES categories
–76 people were diagnosed with an ulcer over the course of the study (documented on endoscopy/radiology exam): 39 duodenal ulcers and 30 gastric ulcers
–ulcers were significantly more common in those in the highest tertile of stress scores (3.5%) vs the lowest (1.6%), with adjusted odds ratio of 2.2 (CI 1.2-3.9, p<.01). This did not change after adjusting for IgG antibodies to H pylori, alcohol consumption, or sleep duration, with a per-point odds ratio for the stress index being 1.19 (CI 1.09-1.31, p<0.001), and a clear dose-response (the higher the stress score, the more likely to have an ulcer)
–the adjusted stress relationship was lower after controlling additionally for SES, with per-point odds ratio for the stress index being 1.17 (CI 1.07-1.29, p<0.001), and further by controlling for smoking, use of NSAIDs and lack of exercise, with per-point odds ratio for the stress index being 1.11 (CI 1.01-1.23, p=0.04).
–there was a similar risk of ulcer related to stress in those who were H pylori positive or negative, or in those both H pylori negative and not on NSAIDs.
–in multivariate analysis, stress, SES, smoking, H pylori infection, and use of NSAIDs were independent predictors of ulcers.

One big plus for this study was its timing: it predated H pylori testing (and treatment), either H2-blockers and subsequently proton-pump inhibitors were available only as prescriptions and not over-the-counter, and the study was done largely before widespread use of low-dose aspirin; all of these factors significantly decrease the confounding that would exist if the study were done now. Purported mechanisms by which stress could cause ulcers include by increases in stomach acid secretion, effects on the hypothalamic-pituitary-adrenal axis (essentially all hormones are affected by stress, many of them mediated by the stress-related cortisol elevations) which can affect healing, hormone-mediated changes in blood flow to the stomach, or cytokine-mediated impairment of mucosal defenses. Some of the stress effect is likely mediated by smoking (which in one study accounted for one-third of the ulcerogenic effect of stress), alcohol or poor sleep (though these latter 2 were not confirmed in the Danish study above). Of note, there was no synergy in the Danish study between stress and H pylori in ulcer development. To me, this is a pretty impressive study despite its being observational, given the quality of the data they collected prospectively, the fact that there is a dose-response curve with each increase in their stress scale associated with increased likelihood of ulcer disease, and their controlling for many known or likely associations for ulcers.

So, not so shocking a finding (I think most of my patients are aware of the link between stress and ulcers….). However, the National Institute of Diabetes and Kidney Diseases of the NIH in 2012 notes “peptic ulcers are not caused by stress”. So, I guess my patients were right all along…

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