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GI- H pylori

Primary Care Corner with Geoffrey Modest MD: H pylori regimens, stratified by clarithromycin sensitivity

18 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent systematic review and network meta-analysis of treatments of H Pylori infections in countries with high vs low clarithromycin resistance (see doi:10.1136/gutjnl-2016-311868). A network meta-analysis is helpful when there are not head-to-head comparisons of all of the therapies, using mathematical assumptions/manipulations to approximate results across studies in an attempt to approximate the likely results if there were such direct comparisons.  There was another recent blog which did a similar analysis of H pylori treatments but was not stratified by clarithromycin sensitivity (see http://blogs.bmj.com/ebm/2015/09/03/primary-care-corner-with-geoffrey-modest-md-h-pylori-regimens/ from the BMJ in 2015).

Details of the current analysis:

  • 117 trials with 32,852 patients analyzing 17 H pylori eradication regimens were included
  • Mean age 48, trials ranged from 58 to 1463 patients, with mean of 281
  • All had documented H pylori infections by urea breath test, histologic or bacterial culture exams, or stool antigen
  • All had documentation of H pylori eradication by intention-to-treat analysis, at least 4 weeks after therapy
  • The authors analyzed results of treatment stratified by clarithromycin resistance, ascertained by a literature review of it prevalence by the countries where the RCTs were done, with a cutpoint of 15% resistance rate.

Results:

  • Compared to a 7-day course of clarithromycin-based triple therapy:
    • Overall: best was 14 days of sequential therapy, OR= 3.74 (2.37-5.96)
    • In areas of high clarithromycin-resistance: best was 14 days of sequential therapy, OR= 6.53 (3.23-13.63). and this did not diminish in the more recent studies where resistance was likely to increase; second best was bismuth, PPI and 2 of amoxacillin/tetracylcine/metronidazone/clarithromycin for 10 or 14 days, with OR 3.6
    • In areas of low clarithromycin-resistance: best was 10 or more days of hybrid therapy, OR= 2.85 (1.58-5.37); second best was continuous therapy (e.g. PPI, amoxacillin and clarithromycin) at least 10 days
    • The lowest efficacy overall was triple therapy with metronidazole for 7 days
    • Overall, better efficacy with longer treatments, which mostly meant 14 days
    • Severe adverse events were rare in all regimens, though happened more often in the longer courses of therapy

Commentary:

  • H pylori infection is unbelievably common, in >50% of world’s population, and is associated with peptic ulcer disease, active gastroduodenal ulcer bleeding, gastric MALT (mucosa-associated lymphoid tissue lymphoma) and >75% of gastric cancers
  • H pylori eradication is recommended in patients on long-term NSAIDs, anti-platelet agents/low-dose ASA, and those with unexplained iron-deficiency anemia or ITP, per the Maastrich IV/Florence Consensus Report in 2012 (see Gut. 2012; 61:646) [as mentioned in prior blogs, see URL at the end of this blog, i saw a dramatic case 20 years ago of a person with intractable steroid-resistant ITP, scheduled for surgery, but the Lancet had a small case report showing benefit of H pylori treatment. so I tested and treated him for H pylori and the ITP melted away, off all meds, within weeks. and without surgery
  • The standard therapy has been a PPI, amoxacillin and clarithromycin or metronidazole, but the effectiveness has been waning.
  • There are some concerns about generalizing the results of the study above. For example all of the 14 day sequential therapy trials were done in Asia. and the inherent and different biases in the different studies, as well as patient characteristics across studies, make confident conclusions difficult (e.g. some studies did not even record smoking prevalence), and studies had different levels of blinding
  • Countries with high clarithroresistance: China, Croatia, France, Greece, Hong Kong, India, Iran, Italy, Japan, Morocco, Spain, Saudi Arabia, Singapore, Turkey
  • Countries with low clarithroresistance: Chile, Ecuador, Finland, Kenya, Korea, Kuwait, Mexico, Taiwan, Thailand, UK, US, Kosovo, Palestine, Romania (last 3 with no recorded resistance rate)
  • Unfortunately, and a bit surprisingly, it was really hard to find out exactly what the therapies were (they were all combined into categories, such a “sequential” or “hybrid” therapies), even after scouring this article and its supplement. My best guess is the following:
    • Sequential therapy for 10 days: first 5 days using PPI (g.omeprazole 20mg) and amoxacillin 1gm; followed by PPI, clarithromycin 500mg and metronidazole 500mg for the remaining 5 days (some studies have substituted tinidazole 500mg for the metronidazole 500mg). all meds given BID
    • Hybrid therapy for 14 days: first 7 days PPI (g.omeprazole 20mg) and amoxacillin 1gm; followed by PPI, amoxacillin 1gm, clarithromycin 500mg and metronidazole 500mg for 7 days (again, some studies substituting tinidazole 500mg for metronidazole 500mg). all meds given BID
    • So, the hybrid therapy seems to be the same as the sequential therapy, with amoxacillinfor the whole course instead of just the first half
  • The sequential therapy (which includes clarithromycin at the end) works even with clarithromycin resistance, with 89% of clarithromycin-resistant strains responding vs 29% with standard therapy — the posited mechanism for resistance being that H pylori had developed efflux channels for clarithro that rapidly remove the drug from the bacteria and that amoxacillin changes the structure of the cell membrane to prevent effective clarithromycin efflux and therefore resistance. (see Ann Intern Med 2007; 146:555-563, and http://blogs.bmj.com/ebm/2013/11/25/primary-care-corner-with-dr-geoffrey-modest-sequential-or-standard-rx-for-h-pylori/)
  • From 9/9/15 blog (see http://blogs.bmj.com/ebm/2015/09/03/primary-care-corner-with-geoffrey-modest-md-h-pylori-regimens/): “and, one very important issue in the US is that we do not have data (at least in Boston) on H pylori sensitivities. Maybe that makes sense. One of our greatest assets in Boston is the wonderful ethnic diversity here. One of the problems (at least as H pylori is concerned) is that H pylori organisms from different parts of the world are here with their different antibiotic sensitivities. So applying averaged sensitivities may not really benefit the individual patient in front of you.”
  • I personally have been using only the 10-day sequential therapy, since it was shown years ago to be superior, though there are some differences in different studies. This therapy is certainly a bit more complicated: I usually have the patient bring back the bottles of pills and either I or a nurse review the regimen in detail. In the very few cases of persistent H pylori infection post-therapy that I have seen (mostly detected by stool antigen testing), I use the bismuth-based regimen: high dose PPI bid, amoxicillin 1gm bid, levofloxacin 500 mg in the evening, and bismuth subcitrate240mg bid for 14 days. So far, so good.
  • But, based on the current study, I will change to the 14-day sequential therapy course. I am certainly concerned that many of my patients are getting too many antibiotics, esp azithromycin (g., see http://blogs.bmj.com/ebm/category/antimicrobial-resistance/) and metronidazole, which are likely to breed resistance in untreated H pylori infections. So, I follow symptoms closely post-therapy, check H pylori antigen when the patient is symptomatic, and retreat with one of the rescue regimens.  If this resistance happens more often, I will switch to the hybrid regimen above.  Also, tinidazole may be more effective than metronidazole, and tinidazole is available in the US but mostly with the disincentive of a Prior Approval……. [Though, the tinidazole may be more effective in the US precisely because we use much much more metronidazole]

 Also so see http://blogs.bmj.com/ebm/category/gi-h-pylori/ has a series of blogs on H Pylori infection, including some suggesting eradication leads to lower incidence of gastric cancer, increased bleeding if H Pylori positive and taking NSAIDs (and some studies showing that eliminating H Pylori leads to lower risk of NSAID-associated bleeding), and a review of several studies of different medication regimens.

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

29 Feb, 16 | by EBM

By Dr. Geoffrey Modest

A recent systematic review/meta-analysis looked at the effects of H pylori eradication and the incidence of gastric cancer (see doi.org/10.1053/j.gastro.2016.01.028). ​

Details:

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

Results:

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

So,

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

http://blogs.bmj.com/ebm/2014/07/15/primary-care-corner-with-geoffrey-modest-md-gastric-cancer-screeningprevention/ which comments on endoscopic screening for high risk patients (again, in Korea, Japan, and China)

http://blogs.bmj.com/ebm/category/gi-h-pylori/ for an array of articles on H pylori regimens (including salvage regimens) and one on the increased risk of GI bleeding in patients with H pylori and taking NSAIDs

 

Primary Care Corner with Geoffrey Modest MD: 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: H pylori Regimens

3 Sep, 15 | by EBM

By. Dr. Geoffrey Modest

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

Background (as noted in prior blogs):

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

Results:

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

So, a few issues:

  • See the array of H pylori articles in prior blogs, including more specific data on some of the more useful regimens (see http://blogs.bmj.com/ebm/category/gi-h-pylori/)
  • I did not include the network meta-analysis results using rantidine bismuth citrate, since this does not appear to be available in the US
  • This network meta-analysis is a mathematical tool to try to look for relative rankings of different therapies which were never directly compared, and suffers from several issues. One of the most important is that h. pylori antibiotic sensitivities range dramatically from one country to another (likely based on prevalent use of the antibiotics for other indications in that country, leading to h pylori resistance), and there are studies showing improved h pylori eradication with targeted therapies based on resistance patterns (as noted in http://blogs.bmj.com/ebm/category/gi-h-pylori/)​
  • One interesting/paradoxical conclusion from this network meta-analysis is that, as opposed to all other comparisons, the shorter duration of PPI and 3 antibiotics fared better than the 10 or 14 day courses of the same regimen
  • Another striking finding was that the bismuth based regimens did somewhat less well, despite a very strong study (see http://blogs.bmj.com/ebm/2015/04/15/primary-care-corner-with-geoffrey-modest-md-h-pylori-rescue-therapy/)
  • As a meta-analysis, it is hard to get more specifics (when they give choices, such as amoxacillin or metronidazole, are there any differences between them. Or between the different 5-nitroimidazoles. Or it there a difference by which probiotics were used. Or is there any difference between 10 and 14 days of therapy.) Also, some of what would seem to be the best regimens had very few participants, so the confidence intervals were very large, and they were under-represented in the final analysis. The studies using probiotics were both fewer in number and of poorer design. And, they were unable to control for smoking and alcohol, potential effect modifiers.
  • And, one very important issue in the US is that we do not have data (at least in Boston) on h pylori sensitivities. Maybe that makes sense. One of our greatest assets in Boston is the wonderful ethnic diversity here. One of the problems (at least as h pylori is concerned) is that h pylori organisms from different parts of the world are here​ with their different antibiotic sensitivities. So applying averaged sensitivities may not really benefit the individual patient in front of you.
  • My best guess, from my own experience and reading, is that I use the 10 day sequential therapy (a bit more complicated: 5 days of PPI bid and amoxacillin 1gm bid, followed by 5 days of PPI bid, clarithromycin 500 bid, and metronidazole 500 bid), and in the very few cases of persistent infection (mostly detected by stool antigen testing), I use the bismuth based regimen: high dose PPIbid, amoxicillin 1gm bid, levofloxacin 500 mg in the evening, and bismuth subcitrate 240mg bid for 14 days. So far, so good…. but I should add that the standard 7 day treatment does well in areas where there is clarithromycin resistance rates of <10% (as in the UK). But lacking data in the US, where there are lots of (unnecessary) azithromycin prescriptions (e.g., see http://blogs.bmj.com/ebm/category/antimicrobial-resistance/ ), I suspect that h pylori resistance is pretty high.

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: H. pylori rescue therapy

15 Apr, 15 | by EBM

By: Dr. Geoffrey Modest 

Most of the cure rates for H. pylori infections are in the 80-90% range, leaving many people with persistent infections.  There have been several articles on rescue therapy, including a recent one with a relatively easy regimen and 90% efficacy (see Aliment Pharmacol Ther 2015; 41: 768–775).  This Spanish/Italian study looked at 200 patients who failed several different initial therapies. details:

–17 hospitals involved in study (15 Spanish, 2 Italian)

–200 patients (mean age 47, 67% women, 13% had ulcers), having had the following prior therapies: 131 patients had  standard PPI-clarithromycin-amoxacillin, 32 with sequential (PPI-amoxacillin x 5 days, then PPI-clarithromycin-metronidazole x 5 days), 37 with quad therapy of PPI-amoxacillin-clarithromycin-metronidazole for 10 days. Failure was defined as a positive 13C-urea breath test 4-8 weeks after therapy.
–all were put on esomeprazole 40mg bid, amoxicillin 1gm bid, levofloxacin 500 mg in the evening, and bismuth subcitrate 240mg bid for 14 days
–primary outcome: eradication rate confirmed by breath test, as above

–results: 180/200 patients (90%), in intention-to-treat analysis, and 175/192 (91%), on per-protocol anaylsis, had cures. Similar results in Spain and Italy, whether diagnosis was peptic ulcer or dyspepsia, or with the type of prior treatment (eg: success in 88.5% on standard triple therapy, 93.8% on sequential therapy, and 91.9% on quad therapy)
–adverse events in 46% (mostly nausea in 17%, diarrhea in 16%, abdominal pain in 15%, metallic taste in 15%), but these were time-limited to the 14 days of treatment and only 6 (3%) felt the adverse effects were “intense”, though none were considered serious.

So, why did this therapy work so well?

–The role of bismuth is likely a major part: bismuth is not itself associated with bacterial resistance, is synergistic with antibiotics, overcomes clarithromycin and levofloxacin resistance, and has efficacy in setting of metronidazole resistance. Purported additional mechanisms of action: decreases mucin viscosity, binds to toxins produced by h pylori, is adherent to gastric epithelium and prevents bacterial colonization, and reduces the bacterial load.

–Although H pylori resistance to fluoroquinolones is increasing (up to 24% in Europe and 13% in Spain), other studies have found that the addition of bismuth dramatically increased eradication rates to a regimen of PPI, amoxacillin, and levofloxacin for 14 days, finding no difference when the h pylori was sensitive to levofloxacin (85%), but when levofloxacin-resistance was present, adding bismuth increased eradication from 37% to 71%.

–The longer 14-day regimen, which has been found in several studies to improve eradication rates

–The use of high dose esomeprazole. ??the role of the high dosage of 40mg (some studies have found 6-10% higher cure rates with higher doses of PPI).  ??the role of the newer PPI (some data that esomeprazole and rabeprazole are better than the first-generation PPIs)

So, this was a large study of patients with documented primary treatment failure and very high response rates to a 14-day course of quadruple-therapy containing bismuth. Although there were no data presented on resistance patterns of the h pylori, it seems very likely that there were many resistant bacteria (given prevailing resistance patterns). Unfortunately, ​in the US we have very little data (none I can find in Boston), where h pylori is basically an imported infection from many different parts of the world with differing resistance patterns. Clinically, i have had good success with the sequential therapy noted above. But this bismuth therapy seems to be a good one for treatment failure. Although it makes sense to use the regimen they prescribe above in order to get their results, I would opt for high dose pantoprazole or omeprazole, given the difficulty in getting esomeprazole through insurance.

Primary Care Corner with Geoffrey Modest MD: H. Pylori Treatment Antibiotic-Guided Therapy

9 Dec, 14 | by EBM

By: Dr. Geoffrey Modest 

In many areas, there is increasing H. Pylori resistance to several antibiotics, including clarithromycin, with decreasing H Pylori eradication rates over time. A recent Korean study assessed the utility of selecting antimicrobial therapy based on antibiotic susceptibility vs standard clarithromycin-based triple therapy (see doi: 10.1038/ajg.2014.222). This issue is important because H pylori is so common, affecting about 50% of the global population (and in our experience, 80-90% of people from high risk countries), is an important risk factor for noncardiac gastric cancer, and there are significant data that H. Pylori elimination reduces the incidence of stomach cancers. in this study 112 patients with H. Pylori and gastric epithelial neoplasia (adenoma and adenocarcinoma)  were randomized to a 7 day course of a proton pump inhibitor (PPI) such as pantoprazole 40mg bid, amoxacillin 1 g bid,  and clarithromycin 500mg bid (PAC) or, if randomized to the pretreatment antimicrobial susceptibility wing, to that regimen if sensitive to clarithromycin but substituting methronidazole 500 mg bid if resistant (PAM) or substituting levofloxacin 400mg daily (PAL) if resistant to both clarithromycin and metronidazole.

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Results:

–Mean age 62, 70% male, 50% with early gastric cancer

–Medication adherence was 98% in both the clarithromycin-based triple therapy (PAC) and the antimicrobial susceptibility-guided therapy

–Resistance pattern: 25% to clarithromycin, 46% to metronidazole, 37% to levofloxacin, 10% to amoxacillin, 3% to tetracycline

–In the antimicrobial susceptibility-guided therapy wing, 78.9% received PAC, 10.5% PAM, and 10.5% PAL therapies (ie most still got PAC)

–Intention-to-treat analysis found 94.7% eradication rate in antimicrobial susceptibility-guided therapy and 71.9% in clarithromycin-based triple therapy (PAC) — this 71.9% is not so different from other studies i’ve seen recently

–In patients with clarithromycin resistance, the eradication rate with antimicrobial susceptibility-guided therapy was 12/12 (100%), but was only 20% in those on PAC

–In those who failed therapy (10 patients involved), they were given antimicrobial susceptibility-guided therapy, 4 of whom got PAL and 6 got PPI bid, metronidazole 500mg tid, tetracycline 500mg qid and bismuth subcitrate 125mg qid for 7 days, with almost 100% success rates

–Adverse events: 8% in each group, esp abdominal pain, nausea, vomiting, bitter taste, and diarrhea, with one patient dropping out of each group because of adverse events

So, this study, done in an area where there was high levels of antibiotic resistance, confirmed pretty clearly that antibiotic resistance matters in terms of eradication of H. Pylori and that with appropriate antibiotics (even for only a 7-day course), there was nearly 100% success. Unfortunately, susceptibility testing is not available here in Boston. My guess is that the pattern of resistance is pretty different here from Korea where this study was done. I would not be surprised if there were even higher rates of metronidazole and levofloxacin resistance here (both being used a lot as monotherapy for, for example, bacterial vaginosis or urinary tract infections/pneumonia respectively, potentially leading to H. Pylori resistance) as well as to clarithromycin (with azithromycin used so often for upper respiratory tract infections). I spoke with a couple of gastroenterologists here whose approach was just to try regular PAC therapy, then choose one of the alternatives if no response, specifically a quadruple therapy with bismuth. However, it seems to me that the Maastricht IV/Florence Consensus report in 2012 makes more sense — that clarithromycin based triple therapy should not be used if clarithromycin resistance rates are higher than 15-20%. This Consensus report does suggest empiric bismuth-containing quadruple therapy as first-line empirical treatment in that case, with levofloxacin-containing triple therapy as second-line, then antimicrobial resistance testing to determine third-line, if failure of second-line (although this Korean study questions that approach some, given the high rates of levofloxacin resistance there). I have been using sequential therapy with great success for many years now. This involves a more complex regimen with the first 5 days being PPI plus amoxacillin 1 gm (both bid), then followed by PPI plus clarithromycin 500mg plus metronidazole 500mg (all bid) for another 5 days. I got this from a study comparing PAC with this therapy (though I used metronidazole instead of tinidazole, since insurance would not cover tinidazole, though that is likely better — less resistance). This study found pretty remarkably that there was a 90% H. Pylori clearance rate in those with documented clarithromycin-resistance, positing that since clarithromycin-resistance is from cells developing efflux channels to clarithromycin and transporting the antibiotic out of bacterial cells, but that the pretreatment with amoxacillin disturbs the bacterial cell wall and prevents this from happening, rendering the bacteria clarithromycin-sensitive (see Ann Intern Med. 2007;146:556-563). Subsequent studies have confirmed 90%+ cure rates with sequential therapy.

What does this all mean?  It seems to me that when an H. Pylori organism is isolated (eg, with a biopsy during endoscopy), therapy should be guided by antibiotic resistance, which should be done routinely in the microbiology lab. but, in primary care, we mostly treat empirically. Given that, it would be really useful to know the general antibiotic susceptibility patterns of H. Pylori to devise the optimal empirical therapy.  Sort of like treating a urinary tract infection. So, I’m not sure why, in Boston, the mecca of the high-concentration, high-cost, high-tech medical-industrial complex, that we don’t have this really useful information…..  in its absence I will continue on my merry way with sequential therapy.

Primary Care Corner with Geoffrey Modest MD: H Pylori Eradication

8 Aug, 14 | by EBM

i posted in July (see here) about the likely utility of treating asymptomatic h pylori infections in high risk populations to decrease the risk of gastric cancer. there has been a subsequent systematic Cochrane review in the BMJ on this subject (see doi: 10.1136/bmj.g3174). 6 RCTs were identified, with inclusion criteria including using eradication therapy at least 7 days and minimum of 2 years of followup. primary outcome of occurrence of gastric cancer. results:

–all but one study conducted in East Asia (other in Colombia), so hard to assess effect in Western populations. only one study with longer-term followup (14.7 years). h pylori eradication rates in low 70% range|
–51 (1.6%) gastric cancers in those receiving eradication therapy vs 76 (2.4%) in 3203 control patients, for  RR 0.66. with assumption that eradication leads to lifelong benefit, the number needed to treat varies from 15 for Chinese men to 245 for US women (this is based on life-time risk of gastric cancer).
–of these gastric cancers, there was only one case of MALT lymphoma (not included in analysis)
–only 3 cases of esophageal cancer, so no significant difference
–only difference in adverse effects was rash in 3.1% on eradication therapy vs 0.1% on placebo

seems to me that the assumption of lifelong protection from h pylori eradication (ie, not get recurrent infection) is borne out by other studies. as noted in blog below, the benefit of eradicating the h pylori infection was in those without precancerous lesions at the time, which suggests that longer followup might yield even better gastric cancer prevention.  so, to me this reinforces the comment to test and treat asymptomatic patients who come from high prevalence h pylori countries (which also seems to track with those at higher risk of gastric cancer).

geoff

 

Primary Care Corner with Dr. Geoffrey Modest: Sequential or standard Rx for H pylori?

25 Nov, 13 | by EBM

previously sent out an article finding that sequential H pylori therapy (5 days of PPI plus amoxicillin 1 g twice a day, followed by 5 days of PPI plus clarithromycin 500 twice a day plus metronidazole 500 twice a day) was superior to standard triple therapy.  This sequential therapy worked even with clarithromycin resistance, with 89% of clarithromycin-resistant strains responding vs 29% with standard therapy. they posited the mechanism for resistance being that h pylori developed efflux channels for clarithro that rapidly remove the drug from the bacteria and that amox changes the structure of the cell membrane to prevent effective clarithromycin efflux and therefore resistance. (see Ann Intern Med 2007; 146:555-563)

 

there was a recent systematic review and meta-analysis in the BMJ assessing the efficacy of sequential versus triple therapy (see  BMJ 2013;347:f4587 doi: 10.1136/bmj.f4587). for this review, 46 randomized control trials were assessed with 5666 patients on sequential therapy versus 7866 on standard therapies.  Results:

–22 studies compared sequential therapy with a seven-day course of standard triple therapy (mostly PPI plus amox plus clarithro, all bid; or PPI plus amox plus metronidazole, all bid).  While in the 5000 patients randomized to each of these 2 groups, sequential therapy resulted in H. pylori eradication in 86.5% versus 71.5% for triple therapy, highly statistically significant

–14 studies compared sequential therapy with triple therapy for 10 days.  2700 patients were divided into the 2 groups with eradication rates of 84.3% for sequential therapy and 75.3% for triple therapy of 10 days duration, a statistically significant result.  No significant differences in adverse effects.

–7 studies compared sequential therapy will triple therapy lasting 14 days. 2500 patients were divided into the 2 groups with 81% eradication rates in each group.  No different in adverse effects

–There was also no difference between sequential therapy and therapy that contained bismuth or with quadruple therapy.

–in pts with clarithro resistance, efficacy of sequential therapy was 73% vs 50% in those with 7 or 10 days of standard therapy,  but no diff with 14 days of standard therapy , or with quadruple therapy or sequential therapy with levoflox instead of clarithro

–in pts with metronidazole resistance, eradication rates for sequential therapy were 86%, vs 62% with 7 day and 59% for 10 day standard therapy, both significant, though the only one was a small study (50/group) of 14day therapy found eradication rate of an unusually low 73% with sequential therapy and 89% with 14-day standard therapy.

–in pts with both metronid and clarithro resistance, studies too small to have generalizable conclusions

so, h pylori infection is really common, at least in boston, and global studies suggest that gastric cancer assoc with h pylori (non-cardia gastric carcinoma and MALT) in 2008 occurred in 470K people in less developed regions and 190K in more developed regions.  data of the standard therapy (per Maastriccht conference in 1997) with PPI, clarithro, and either amox or metronidazole suggest waning efficacy over time.  In Europe, resistance to clarithromycin is 17.5%, to levofloxacin is 14%, and metronidazole is 35%.  it would be very useful to use local resistance patterns as a way of choosing empiric therapy. in 2007 when the first sequential therapy article came out (above), i called several endoscopists at boston medical center and no one had data on local resistance patterns.  i called again today and this is still true. Their guess is that resistance is very common here (perhaps in the 30-50% range!!!), though they still mostly prescribe the 10 day course of standard therapy, without great results. one big issue here is that NONE of the studies have been done in the US, again clouding the picture of what we should do. I personally have been prescribing the sequential therapy since that annals article in 2007, since I suspected that antibiotic resistance was high given the commonplace use of metronidazole and clarithromycin locally for other infections. the only problem is that it is a more complex regimen and takes a while to explain the therapy, for which I made a written handout, which elineates day-to-day therapy. from the new bmj article, perhaps standard therapy for 14 days is equivalent (again, this may not be true if our resistance patterns are really different…. who knows??)

 

Geoff

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