Random blinded allocation (1:1) to either 30 mg lansoprazole (n=172) twice daily or matched placebo (n=174) twice daily for 16 weeks of patients with persistent throat symptoms.
Eligible patients had persistent (>6 weeks) unexplained throat symptoms—principally hoarseness, throat pain, globus sensation, throat clearing, postnasal secretions or excess mucus, cough, or choking sensation
Primary outcome was symptomatic response at 16 weeks measured using the total reflux symptom index (RSI) score.
No evidence was found of benefit from PPI treatment in patients with persistent throat symptoms. RSI scores were similar between the lansoprazole and placebo groups after 16 weeks of treatment and at the 12 month follow-up.
Improvements (reduction in RSI score) were observed in both groups—score at 16 weeks: lansoprazole 17.4 (15.5 to19.4) and placebo 15.6 (13.8 to 17.3). No statistically significant difference was found between the treatment arms. Furthermore, “no trends were in favour of lansoprazole.”
Limitation: “Our trial could be criticised for lacking any objective measure of GORD within the methodology or for employing any such test as an inclusion criteria. However, we did address the use of PPIs in an empirical setting, which was a near universal practice at the time of our study.”
My take (borrowed in part from authors): “No evidence supports the empirical use of PPIs to treat persistent throat and voice symptoms.” Despite this finding, “old habits die hard” and I predict that it will be a long time before this finding is widely adopted into clinical practice.
In the June issue of Gastroenterology (158: 2015-16), a tribute to George Sachs (1935-2019) recognizes his work in the field of gastroenterology and his development of proton pump inhibitors (PPIs).
Much more work remains as ~30% of patients with gastroesophageal reflux remain symptomatic despite PPI therapy. In the same issue, IW-3718, a bile acid sequestrant colsevelam with a gastric-retentive formulation was studied in 280 patients (MF Vaez et al. Gastroenterol 2020; 158: 2017-19).
Methods: The authors performed a multicenter, double-blind, placebo-controlled 8-weel treatment trial (2016-17); patients received the study drug (500, 1000, 1500 mg) or placebo twice daily. The authors enrolled symptomatic patients (≥4 times per week) with erosive esophagitis or pathologic reflux based on Bravo study (pH<4 for ≥4.2% during at least one 24-hour period). They continued PPI therapy which they had been receiving for a minimum of 8 weeks prior to starting study medication.
Improvement in heartburn severity scores for placebo, 500, 1000, and 1500 mg groups: 46%, 49%, 55%, and 58%. The 11.9% difference between 1500 mg group compared to placebo reached statistical significance (P=.04)
There was an improvement in weekly regurgitation frequency score as well from baseline to week 8 in 1500 mg group of 17.5% compared to placebo.
No serious drug related serious adverse events were identified. Constipation was noted in 8% of study drug recipients compared 7% for placebo recipients.
Limitations: lack of a centralized review for endoscopy images, high placebo response rate, once daily use of PPI in study, and problems with overlap of functional symptoms
My take: This study shows why a placebo control is needed in reflux studies. While IW-3718 at higher doses was effective, its response appears much less notable when compared with placebo-recipients.
A recent study (SD Delshad, CV Almario et al. Gastroenterol 2020; 158: 1250-61) used survey data from an APP, MyGiHealth, to assess prevalence of reflux symptoms and symptoms that had not responded to proton pump inhibitor treatment.
In 2015, among 71,812 participants, 32,878 (44.1%) reported reflux symptoms previously and 23,039 (30.9%) reported reflux symptoms in previous week
35% with reflux symptoms were currently receiving treatment: 55% PPIs, 24% H2RAs, and 24% antacids
Of the 3229 taking daily PPIs, 54% reported persistent reflux symptoms (≥2 days per week)
Age range of respondents was 33% for 18-29, 27% for 30-39, 17% for 40-49, 15% for 50-59, and 8% ≥60
Potential selection bias as there was only a 5.5% response rate among the entire eligible population of 1.3 million
Reflux symptoms frequently is not due to reflux disease
My take: There are a lot of folks with reflux symptoms and many have ongoing symptoms despite treatment; hence, lots of opportunity to help (and job security)
PPIs: Good News on Safety Large randomized double-blind study of pantoprazole: “we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections.”
“One sick singer attended choir practice, infecting 52 others, two of whom died. A study released by the C.D.C. shows that self-isolation and tracing efforts helped contain the outbreak.” Only 8 of the 61 choir members did not get sick.
A recent retrospective study (A Rengarajan et al. Clin Gastroenterol Hepatol 2020; 18: 589-95), with a cohort of 371 patients (mean age 54 years) shows how impedance testing may help identify patients who are likely to respond to reflux management when pH probe testing is equivocal. The cohort included adults with persistent reflux symptoms. Response to antireflux therapy was defined as >50% improvement in esophageal symptoms.
107 (28.8%) had pathologic acid exposure time (AET) (pH<4 for >6%)
234 (63.1%) had abnormal mean nocturnal baseline impedance (MNBI) (<2292 ohms). MNBI was calculated using baseline values at 10-minute periods between 1-3 am from the 5 cm channel to correspond to total distal AET.
Figure 1, shows the combined use of AET and MNBI. Only 106/107 patients with AET>6, had an abnormal MNBI. In the borderline category of AET 4-6%, 62/68 (91.2%) had abnormal MNBI values. In those with AET <4, MNBI was abnormal in 66/196 (33.7%)
Response to Treatment:
Among patients with AET >6, 66/89 (74%) responded to medical therapy and 18/23 (78%) responded to surgical therapy; among patients with AET 4-6%, 37/56 (66%) responded to medical therapy and 14/17 (82%) responded to surgical therapy. In those with AET <4, 39/185 (21%) responded to medical therapy and 16/23 (70%) responded to surgical therapy
Among patients with a low MNBI, 119/198 (60%) responded to medical therapy and 41/50 (82%) to surgical therapy. In those with a normal MNBI, 23/132 (17%) responded to medical therapy and 7/13 (54%) responded to surgical treatment
In those with AET >6, 84/111 (76%) responded to treatment. For those with AET 4-6%, of those with low MNBI, 49/67 (73%), responded (similar to those with AET >6%). In those with low MNBI and AET <4, 27/70 (39%) responded to treatment
28/138 (20.2%) with normal AET <4 and with normal MNBI responded to treatment
My take: The big takeaway is that all of our tests for pathologic reflux are highly flawed; impedance may (to a small degree) help stratify patients with equivocal evaluation based on AET. Normal tests do not exclude response treatment (especially surgery).
A recent prospective longitudinal cohort study (J Franken et al. JPGN 2020; 70: e41-47) examined the development of gastroesophageal reflux (GER) in 50 children who underwent gastrostomy tube (GT) placement between 2012-2014.
GER symptoms were present before and after GT placement: in 44% and 40% respectively.
Among the 25 who underwent pre- and post-operative impedance-pH analysis
there was not a significant change in acid exposure: 6.2% vs. 6.1%
there was not a significant change in reflux episodes
Prior to GT placement, 18 of 25 (72%) had pathologic reflux. Afterwards, 18 of 25 (72%) had pathologic reflux –though this included 4 with new onset reflux and 4 with resolved reflux
My take: This study shows that reflux symptoms and documented reflux are commonplace in children undergoing GT placement. Based on this limited sample size, it appears that GER does not appreciably change following GT placement.
In both kids and adults, individuals presenting with complaints of reflux more often have other problems like functional heartburn or reflux hypersensitivity (see posts below). A recent prospective, cross-sectional study (LB Mahoney et al. JPGN 2020; 70: 31-36) provides data that further shows that abnormal pH-impedance (pH-MII) testing does NOT predict reduced quality of life (QOL) in children with reflux symptoms (n=82).
38% had abnormal pH-MII testing; however, there were no significant differences in QOL scores on any of the tested questionairres between those with normal or abnormal pH-MII studies.
Subjects with gross esophagitis on EGD reported significantly worse QOL scores. Microscopic esophagitis was not associate with differences in QOL scores.
The implication of this study is that reflux without esophagitis is NOT a driver of abnormal QOL parameters; instead, functional GI disorders are likely more important.
My take: This study makes it clear that gross endoscopic findings are much more consequential than abnormal pH-MII studies.
Now, a retrospective study (LB Mahoney, E Liu, R Rosen. JPGN 2019; 69: 678-81) found no difference in the rate of reflux in 18 children who were with gastrostomy-tube dependent.
In this study, 24-hour multichannel intraluminal impedance with pH monitoring (MII-pH) examine reflux events in children receiving exclusive enteral nutrition with a combination of daytime bolus feeds and overnight continuous feeds; each patient served as their own control. this included 6 with prior fundoplication.
There was no difference in rate of reflux events when comparing bolus feedings and drip (aka continuous) feedings.
The limitations in this study include the small sample size and retrospective design. The authors estimate that to achieve adequate power (80% power) to detect a risk ratio of 1.2 would require 211 patients.
My take: This study and other small studies challenge the assumption that drip feedings are safer. Though, until a larger prospective study is performed, we will not know.
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A recent retrospective study (FWT Vergouwe et al. JPGN 2019; 69: 515-22) with 57 children with esophageal atresia (EA) found most children have a normal reflux index.
This study, analyzing data between 2012-2017, reviewed all 24-hour pH-impedance (MII) studies in children at ≤18 months and 8 year olds with EA. “All children with EA born in our hospital are offered a 24-hour pH-MII study at the age of 0.5 years and 8 years.” In this institution, PPI treatment is given for at least 6 months after surgery. Of the 57 in the cohort, 20 had completed pH-MII at <18 months of age and 32 at age 8 years.
In children ≤18 months of age, median reflux index was 2.6% (abnormal in 2), median number of retrograde boluses was 61 (62% nonacid, 58% mixed)
In the older cohort (~8 years of age), median reflux index was 0.3% (abnormal in 4) and median number of retrograde boluses was 21 (64% nonacid, 75% mixed)
Overall, 10 of 57 children (17.5%) had GERD with reflux index >7% (n=6) or positive SI/SAP (n=4). The authors note that much higher rates of GERD have been found in prior studies. If they included children with fundoplication who were considered as having GERD (prior to fundoplication), then the GERD rate was 32%.
My take: This study showed that reflux in this cohort of children with EA was similar to the general population and likely indicates that a substantial portion of patients with EA do not need indefinite PPI therapy. In children with more complex EA, PPI therapy is likely to be more beneficial.
A recent study (SJ Spechler et al. NEJM 2019; 381: 1513-23) on first glance appears to support surgery as more effective than medical treatment for refractory heartburn.
Only ~20% of enrolled patients were included in the reported outcomes!
Here’s what happened. Among a cohort of VA patients (n=360, mean age 48 years) who were reportedly refractory to PPI-treatment:
78 were excluded during prerandomization
42 had relief of their heartburn during a 2-week omeprazole lead-in (20 mg BID)
70 did not complete trial procedures
23 had non-GERD disorders
99 had functional heartburn
This left 78 patients who underwent randomization. All patients in this highly-selected group had undergone endoscopy with biopsy, impedance-pH testing, and esophageal manometry. 18 of 27 (67%) had treatment success with surgery compared to 7 of 25 patients treated with baclofen/PPI and 3 of 26 with control medical treatment (PPI alone).
Careful evaluation is needed in any patient with refractory heartburn, especially if contemplating surgery. Most will either respond to PPI treatment or have a disorder other than reflux; the authors note that 122 patients (out of 360 patients) did NOT have reflux –99 had functional heartburn.
Careful instruction in PPI use can be helpful. Omeprazole and similar agents should be taken 30 minutes before meals.
The authors noted that in addition to reflux, that reflux hypersensitivity can “respond to fundoplication…treatment success was 71% among the 14 with reflux hypersensitivity and 62% among the 13 with abnormal acid reflux.”
Limitations: The VA population is not representative of the general population; this trial had a predominance of white males. Also, it is hard to exclude that some of the ‘success’ of the procedure could relate to a powerful placebo response.
My take: This trial reinforces the notion that reflux surgery is helpful in very few highly-selected patients.